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Biophysical Characterization and Molecular Engineering of Multidomain Proteins

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 46073

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Prof. Dr. Koichi Kato

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Department of Creative Research, Biomolecular Organization Research Group, Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki 444-8787, Japan
Interests: biomolecular ordering; glycobiophysics; biomolecular NMR spectroscopy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Takayuki Uchihashi

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Laboratory of Biomolecular Dynamics and Function, Department of Physics, Nagoya University, Nagoya 464-8602, Japan
Interests: single-molecule biophysics; protein dynamics; protein assembly; atomic force microscopy; optical microscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Most proteins working in living systems consist of evolutionarily acquired multiple domains, which cooperate with one another and exhibit synergistic actions, thereby exerting sophisticated functions typified by allosteric regulations. Structural proteomics, in conjunction with bioinformatics, have achieved systematic classification and the prediction of tertiary structures of individual domains as globular structural units. However, it remains challenging to delineate or predict the overall conformations of multidomain proteins, primarily because of their dynamic properties. In this class of proteins, the globular domains are connected through flexible linkers, and, consequently, are mobile to a greater or lesser extent, which enables variable spatial arrangements of the domains, depending on their cognate ligands or binding partners, as well as solution conditions such as pH. Therefore, to elucidate the mechanisms underlying multidomain protein functions, applications of experimental and theoretical methods are necessary in order to provide dynamic views of domain–domain interactions. This line of approach will offer a structural basis for the design and engineering of multidomain proteins.

As the guest editors of this Special Issue, titled “Biophysical Characterization and Molecular Engineering of Multidomain Proteins”, in IJMS, we welcome contributions from various research fields, including biophysics, bioinformatics, biomolecular engineering, and molecular phylogenetics. Formats for submissions include original research reports, reviews/mini-reviews, perspectives/opinions, and methodology articles.

Prof. Dr. Koichi Kato
Prof. Dr. Takayuki Uchihashi
Guest Editors

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Published Papers (14 papers)

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10 pages, 1447 KiB

Open AccessArticle

Dynamic Assembly/Disassembly of Staphylococcus aureus FtsZ Visualized by High-Speed Atomic Force Microscopy

by Junso Fujita, Shogo Sugiyama, Haruna Terakado, Maho Miyazaki, Mayuki Ozawa, Nanami Ueda, Natsuko Kuroda, Shun-ichi Tanaka, Takuya Yoshizawa, Takayuki Uchihashi and Hiroyoshi Matsumura

Int. J. Mol. Sci. 2021, 22(4), 1697; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041697 - 08 Feb 2021

Cited by 4 | Viewed by 2413

Abstract

FtsZ is a key protein in bacterial cell division and is assembled into filamentous architectures. FtsZ filaments are thought to regulate bacterial cell division and have been investigated using many types of imaging techniques such as atomic force microscopy (AFM), but the time scale of the method was too long to trace the filament formation process. Development of high-speed AFM enables us to achieve sub-second time resolution and visualize the formation and dissociation process of FtsZ filaments. The analysis of the growth and dissociation rates of the C-terminal truncated FtsZ (FtsZt) filaments indicate the net growth and dissociation of FtsZt filaments in the growth and dissociation conditions, respectively. We also analyzed the curvatures of the full-length FtsZ (FtsZf) and FtsZt filaments, and the comparative analysis indicated the straight-shape preference of the FtsZt filaments than those of FtsZf. These findings provide insights into the fundamental dynamic behavior of FtsZ protofilaments and bacterial cell division. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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13 pages, 16103 KiB

Open AccessArticle

Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling

by Hisham M. Dokainish and Yuji Sugita

Int. J. Mol. Sci. 2021, 22(1), 270; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010270 - 29 Dec 2020

Cited by 10 | Viewed by 3103

Abstract

Conformational transitions in multidomain proteins are essential for biological functions. The Apo conformations are typically open and flexible, while the Holo states form more compact conformations stabilized by protein-ligand interactions. Unfortunately, the atomically detailed mechanisms for such open-closed conformational changes are difficult to be accessed experimentally as well as computationally. To simulate the transitions using atomistic molecular dynamics (MD) simulations, efficient conformational sampling algorithms are required. In this work, we propose a new approach based on generalized replica-exchange with solute tempering (gREST) for exploring the open-closed conformational changes in multidomain proteins. Wherein, selected surface charged residues in a target protein are defined as the solute region in gREST simulation and the solute temperatures are different in replicas and exchanged between them to enhance the domain motions. This approach is called gREST selected surface charged residues (gREST_SSCR) and is applied to the Apo and Holo states of ribose binding protein (RBP) in solution. The conformational spaces sampled with gREST_SSCR are much wider than those with the conventional MD, sampling open-closed conformational changes while maintaining RBP domains’ stability. The free-energy landscapes of RBP in the Apo and Holo states are drawn along with twist and hinge angles of the two moving domains. The inter-domain salt-bridges that are not observed in the experimental structures are also important in the intermediate states during the conformational changes. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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14 pages, 3143 KiB

Open AccessArticle

PV1 Protein from Plasmodium falciparum Exhibits Chaperone-Like Functions and Cooperates with Hsp100s

by Kazuaki Hakamada, Manami Nakamura, Rio Midorikawa, Kyosuke Shinohara, Keiichi Noguchi, Hikaru Nagaoka, Eizo Takashima, Ken Morishima, Rintaro Inoue, Masaaki Sugiyama, Akihiro Kawamoto and Masafumi Yohda

Int. J. Mol. Sci. 2020, 21(22), 8616; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228616 - 16 Nov 2020

Cited by 5 | Viewed by 2248

Abstract

Plasmodium falciparum parasitophorous vacuolar protein 1 (PfPV1), a protein unique to malaria parasites, is localized in the parasitophorous vacuolar (PV) and is essential for parasite growth. Previous studies suggested that PfPV1 cooperates with the Plasmodium translocon of exported proteins (PTEX) complex to export various proteins from the PV. However, the structure and function of PfPV1 have not been determined in detail. In this study, we undertook the expression, purification, and characterization of PfPV1. The tetramer appears to be the structural unit of PfPV1. The activity of PfPV1 appears to be similar to that of molecular chaperones, and it may interact with various proteins. PfPV1 could substitute CtHsp40 in the CtHsp104, CtHsp70, and CtHsp40 protein disaggregation systems. Based on these results, we propose a model in which PfPV1 captures various PV proteins and delivers them to PTEX through a specific interaction with HSP101. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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15 pages, 3441 KiB

Open AccessArticle

Development of a Protein Scaffold for Arginine Sensing Generated through the Dissection of the Arginine-Binding Protein from Thermotoga maritima

by Giovanni Smaldone, Alessia Ruggiero, Nicole Balasco and Luigi Vitagliano

Int. J. Mol. Sci. 2020, 21(20), 7503; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207503 - 12 Oct 2020

Cited by 3 | Viewed by 2200

Abstract

Arginine is one of the most important nutrients of living organisms as it plays a major role in important biological pathways. However, the accumulation of arginine as consequence of metabolic defects causes hyperargininemia, an autosomal recessive disorder. Therefore, the efficient detection of the arginine is a field of relevant biomedical/biotechnological interest. Here, we developed protein variants suitable for arginine sensing by mutating and dissecting the multimeric and multidomain structure of Thermotoga maritima arginine-binding protein (TmArgBP). Indeed, previous studies have shown that TmArgBP domain-swapped structure can be manipulated to generate simplified monomeric and single domain scaffolds. On both these stable scaffolds, to measure tryptophan fluorescence variations associated with the arginine binding, a Phe residue of the ligand binding pocket was mutated to Trp. Upon arginine binding, both mutants displayed a clear variation of the Trp fluorescence. Notably, the single domain scaffold variant exhibited a good affinity (~3 µM) for the ligand. Moreover, the arginine binding to this variant could be easily reverted under very mild conditions. Atomic-level data on the recognition process between the scaffold and the arginine were obtained through the determination of the crystal structure of the adduct. Collectively, present data indicate that TmArgBP scaffolds represent promising candidates for developing arginine biosensors. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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21 pages, 6103 KiB

Open AccessArticle

Domain Organization in Plant Blue-Light Receptor Phototropin2 of Arabidopsis thaliana Studied by Small-Angle X-ray Scattering

by Masayoshi Nakasako, Mao Oide, Yuki Takayama, Tomotaka Oroguchi and Koji Okajima

Int. J. Mol. Sci. 2020, 21(18), 6638; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186638 - 10 Sep 2020

Cited by 4 | Viewed by 2531

Abstract

Phototropin2 (phot2) is a blue-light (BL) receptor protein that regulates the BL-dependent activities of plants for efficient photosynthesis. Phot2 is composed of two light-oxygen-voltage sensing domains (LOV1 and LOV2) to absorb BL, and a kinase domain. Photo-activated LOV domains, especially LOV2, play a major role in photo-dependent increase in the phosphorylation activity of the kinase domain. The atomic details of the overall structure of phot2 and the intramolecular mechanism to convert BL energy to a phosphorylation signal remain unknown. We performed structural studies on the LOV fragments LOV1, LOV2, LOV2-linker, and LOV2-kinase, and full-length phot2, using small-angle X-ray scattering (SAXS). The aim of the study was to understand structural changes under BL irradiation and discuss the molecular mechanism that enhance the phosphorylation activity under BL. SAXS is a suitable technique for visualizing molecular structures of proteins in solution at low resolution and is advantageous for monitoring their structural changes in the presence of external physical and/or chemical stimuli. Structural parameters and molecular models of the recombinant specimens were obtained from SAXS profiles in the dark, under BL irradiation, and after dark reversion. LOV1, LOV2, and LOV2-linker fragments displayed minimal structural changes. However, BL-induced rearrangements of functional domains were noted for LOV2-kinase and full-length phot2. Based on the molecular model together with the absorption measurements and biochemical assays, we discuss the intramolecular interactions and domain motions necessary for BL-enhanced phosphorylation activity of phot2. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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17 pages, 1830 KiB

Open AccessArticle

Structural Characterization of Covalently Stabilized Human Cystatin C Oligomers

by Magdalena Chrabąszczewska, Adam K. Sieradzan, Sylwia Rodziewicz-Motowidło, Anders Grubb, Christopher M. Dobson, Janet R. Kumita and Maciej Kozak

Int. J. Mol. Sci. 2020, 21(16), 5860; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165860 - 15 Aug 2020

Cited by 3 | Viewed by 2839

Abstract

Human cystatin C (HCC), a cysteine-protease inhibitor, exists as a folded monomer under physiological conditions but has the ability to self-assemble via domain swapping into multimeric states, including oligomers with a doughnut-like structure. The structure of the monomeric HCC has been solved by X-ray crystallography, and a covalently linked version of HCC (stab-1 HCC) is able to form stable oligomeric species containing 10–12 monomeric subunits. We have performed molecular modeling, and in conjunction with experimental parameters obtained from atomic force microscopy (AFM), transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) measurements, we observe that the structures are essentially flat, with a height of about 2 nm, and the distance between the outer edge of the ring and the edge of the central cavity is ~5.1 nm. These dimensions correspond to the height and diameter of one stab-1 HCC subunit and we present a dodecamer model for stabilized cystatin C oligomers using molecular dynamics simulations and experimentally measured parameters. Given that oligomeric species in protein aggregation reactions are often transient and very highly heterogeneous, the structural information presented here on these isolated stab-1 HCC oligomers may be useful to further explore the physiological relevance of different structural species of cystatin C in relation to protein misfolding disease. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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13 pages, 2462 KiB

Open AccessArticle

An EPR Study on the Interaction between the Cu(I) Metal Binding Domains of ATP7B and the Atox1 Metallochaperone

by Michael Zaccak, Zena Qasem, Lada Gevorkyan-Airapetov and Sharon Ruthstein

Int. J. Mol. Sci. 2020, 21(15), 5536; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155536 - 02 Aug 2020

Cited by 9 | Viewed by 3109

Abstract

Copper’s essentiality and toxicity mean it requires a sophisticated regulation system for its acquisition, cellular distribution and excretion, which until now has remained elusive. Herein, we applied continuous wave (CW) and pulsed electron paramagnetic resonance (EPR) spectroscopy in solution to resolve the copper trafficking mechanism in humans, by considering the route travelled by Cu(I) from the metallochaperone Atox1 to the metal binding domains of ATP7B. Our study revealed that Cu(I) is most likely mediated by the binding of the Atox1 monomer to metal binding domain 1 (MBD1) and MBD4 of ATP7B in the final part of its extraction pathway, while the other MBDs mediate this interaction and participate in copper transfer between the various MBDs to the ATP7B membrane domain. This research also proposes that MBD1-3 and MBD4-6 act as two independent units. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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12 pages, 2687 KiB

Open AccessArticle

NMR Characterization of Conformational Interconversions of Lys48-Linked Ubiquitin Chains

by Methanee Hiranyakorn, Saeko Yanaka, Tadashi Satoh, Thunchanok Wilasri, Benchawan Jityuti, Maho Yagi-Utsumi and Koichi Kato

Int. J. Mol. Sci. 2020, 21(15), 5351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155351 - 28 Jul 2020

Cited by 2 | Viewed by 2502

Abstract

Ubiquitin (Ub) molecules can be enzymatically connected through a specific isopeptide linkage, thereby mediating various cellular processes by binding to Ub-interacting proteins through their hydrophobic surfaces. The Lys48-linked Ub chains, which serve as tags for proteasomal degradation, undergo conformational interconversions between open and closed states, in which the hydrophobic surfaces are exposed and shielded, respectively. Here, we provide a quantitative view of such dynamic processes of Lys48-linked triUb and tetraUb in solution. The native and cyclic forms of Ub chains are prepared with isotope labeling by in vitro enzymatic reactions. Our comparative NMR analyses using monomeric Ub and cyclic diUb as reference molecules enabled the quantification of populations of the open and closed states for each Ub unit of the native Ub chains. The data indicate that the most distal Ub unit in the Ub chains is the most apt to expose its hydrophobic surface, suggesting its preferential involvement in interactions with the Ub-recognizing proteins. We also demonstrate that a mutational modification of the distal end of the Ub chain can remotely affect the solvent exposure of the hydrophobic surfaces of the other Ub units, suggesting that Ub chains could be unique design frameworks for the creation of allosterically controllable multidomain proteins. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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16 pages, 2813 KiB

Open AccessArticle

An Off-the-Shelf Approach for the Production of Fc Fusion Proteins by Protein Trans-Splicing towards Generating a Lectibody In Vitro

by Anniina Jaakkonen, Gerrit Volkmann and Hideo Iwaï

Int. J. Mol. Sci. 2020, 21(11), 4011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114011 - 03 Jun 2020

Cited by 7 | Viewed by 6482

Abstract

Monoclonal antibodies, engineered antibodies, and antibody fragments have become important biological therapeutic platforms. The IgG format with bivalent binding sites has a modular structure with different biological roles, i.e., effector and binding functions, in different domains. We demonstrated the reconstruction of an IgG-like domain structure in vitro by protein ligation using protein trans-splicing. We produced various binding domains to replace the binding domain of IgG from Escherichia coli and the Fc domain of human IgG from Brevibacillus choshinensis as split-intein fusions. We showed that in vitro protein ligation could produce various Fc-fusions at the N-terminus in vitro from the independently produced domains from different organisms. We thus propose an off-the-shelf approach for the combinatorial production of Fc fusions in vitro with several distinct binding domains, particularly from naturally occurring binding domains. Antiviral lectins from algae are known to inhibit virus entry of HIV and SARS coronavirus. We demonstrated that a lectin could be fused with the Fc-domain in vitro by protein ligation, producing an IgG-like molecule as a “lectibody”. Such an Fc-fusion could be produced in vitro by this approach, which could be an attractive method for developing potential therapeutic agents against rapidly emerging infectious diseases like SARS coronavirus without any genetic fusion and expression optimization. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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Review

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18 pages, 4699 KiB

Open AccessReview

Roles of the C-Terminal Amino Acids of Non-Hexameric Helicases: Insights from Escherichia coli UvrD

by Hiroaki Yokota

Int. J. Mol. Sci. 2021, 22(3), 1018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031018 - 20 Jan 2021

Cited by 4 | Viewed by 2050

Abstract

Helicases are nucleic acid-unwinding enzymes that are involved in the maintenance of genome integrity. Several parts of the amino acid sequences of helicases are very similar, and these quite well-conserved amino acid sequences are termed “helicase motifs”. Previous studies by X-ray crystallography and single-molecule measurements have suggested a common underlying mechanism for their function. These studies indicate the role of the helicase motifs in unwinding nucleic acids. In contrast, the sequence and length of the C-terminal amino acids of helicases are highly variable. In this paper, I review past and recent studies that proposed helicase mechanisms and studies that investigated the roles of the C-terminal amino acids on helicase and dimerization activities, primarily on the non-hexermeric Escherichia coli (E. coli) UvrD helicase. Then, I center on my recent study of single-molecule direct visualization of a UvrD mutant lacking the C-terminal 40 amino acids (UvrDΔ40C) used in studies proposing the monomer helicase model. The study demonstrated that multiple UvrDΔ40C molecules jointly participated in DNA unwinding, presumably by forming an oligomer. Thus, the single-molecule observation addressed how the C-terminal amino acids affect the number of helicases bound to DNA, oligomerization, and unwinding activity, which can be applied to other helicases. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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12 pages, 2688 KiB

Open AccessReview

Role of NMR in High Ordered Structure Characterization of Monoclonal Antibodies

by Yuji Tokunaga and Koh Takeuchi

Int. J. Mol. Sci. 2021, 22(1), 46; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010046 - 22 Dec 2020

Cited by 9 | Viewed by 4682

Abstract

Obtaining high ordered structure (HOS) information is of importance to guarantee the efficacy and safety of monoclonal antibodies (mAbs) in clinical application. Assessment of HOS should ideally be performed in a non-invasive manner under their formulated storage conditions, as any perturbation can introduce unexpected detritions. However, most of the currently available techniques only indirectly report HOS of mAbs and/or require a certain condition to conduct the analyses. Besides, the flexible multidomain architecture of mAbs has hampered atomic-resolution structural analyses using X-ray crystallography and cryo-electron microscopy. In contrast, the ability of nuclear magnetic resonance (NMR) spectroscopy to structurally analyze biomolecules in various conditions in a non-invasive and quantitative manner is suitable to meet the needs. However, the application of NMR to mAbs is not straightforward due to the high molecular weight of the system. In this review, we will discuss how NMR techniques have been applied to HOS analysis of mAbs, along with the recent advances of the novel ¹⁵N direct detection NMR strategy that allows for obtaining the structural fingerprint of mAbs at lower temperatures under multiple formulation conditions. The potential application of these NMR strategies will benefit next-generation mAbs, such as antibody-drug conjugates and bispecific antibodies. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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17 pages, 1669 KiB

Open AccessReview

Large Multidomain Protein NMR: HIV-1 Reverse Transcriptase Precursor in Solution

by Tatiana V. Ilina, Zhaoyong Xi, Teresa Brosenitsch, Nicolas Sluis-Cremer and Rieko Ishima

Int. J. Mol. Sci. 2020, 21(24), 9545; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249545 - 15 Dec 2020

Cited by 1 | Viewed by 2228

Abstract

NMR studies of large proteins, over 100 kDa, in solution are technically challenging and, therefore, of considerable interest in the biophysics field. The challenge arises because the molecular tumbling of a protein in solution considerably slows as molecular mass increases, reducing the ability to detect resonances. In fact, the typical ¹H-¹³C or ¹H-¹⁵N correlation spectrum of a large protein, using a ¹³C- or ¹⁵N-uniformly labeled protein, shows severe line-broadening and signal overlap. Selective isotope labeling of methyl groups is a useful strategy to reduce these issues, however, the reduction in the number of signals that goes hand-in-hand with such a strategy is, in turn, disadvantageous for characterizing the overall features of the protein. When domain motion exists in large proteins, the domain motion differently affects backbone amide signals and methyl groups. Thus, the use of multiple NMR probes, such as ¹H, ¹⁹F, ¹³C, and ¹⁵N, is ideal to gain overall structural or dynamical information for large proteins. We discuss the utility of observing different NMR nuclei when characterizing a large protein, namely, the 66 kDa multi-domain HIV-1 reverse transcriptase that forms a homodimer in solution. Importantly, we present a biophysical approach, complemented by biochemical assays, to understand not only the homodimer, p66/p66, but also the conformational changes that contribute to its maturation to a heterodimer, p66/p51, upon HIV-1 protease cleavage. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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20 pages, 4858 KiB

Open AccessReview

PDI Family Members as Guides for Client Folding and Assembly

by Shingo Kanemura, Motonori Matsusaki, Kenji Inaba and Masaki Okumura

Int. J. Mol. Sci. 2020, 21(24), 9351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249351 - 08 Dec 2020

Cited by 17 | Viewed by 3016

Abstract

Complicated and sophisticated protein homeostasis (proteostasis) networks in the endoplasmic reticulum (ER), comprising disulfide catalysts, molecular chaperones, and their regulators, help to maintain cell viability. Newly synthesized proteins inserted into the ER need to fold and assemble into unique native structures to fulfill their physiological functions, and this is assisted by protein disulfide isomerase (PDI) family. Herein, we focus on recent advances in understanding the detailed mechanisms of PDI family members as guides for client folding and assembly to ensure the efficient production of secretory proteins. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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19 pages, 1464 KiB

Open AccessReview

Roles of Membrane Domains in Integrin-Mediated Cell Adhesion

by Daniel Lietha and Tina Izard

Int. J. Mol. Sci. 2020, 21(15), 5531; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155531 - 01 Aug 2020

Cited by 28 | Viewed by 5648

Abstract

The composition and organization of the plasma membrane play important functional and regulatory roles in integrin signaling, which direct many physiological and pathological processes, such as development, wound healing, immunity, thrombosis, and cancer metastasis. Membranes are comprised of regions that are thick or thin owing to spontaneous partitioning of long-chain saturated lipids from short-chain polyunsaturated lipids into domains defined as ordered and liquid-disorder domains, respectively. Liquid-ordered domains are typically 100 nm in diameter and sometimes referred to as lipid rafts. We posit that integrin β senses membrane thickness and that mechanical force on the membrane regulates integrin activation through membrane thinning. This review examines what we know about the nature and mechanism of the interaction of integrins with the plasma membrane and its effects on regulating integrins and its binding partners. Full article

(This article belongs to the Special Issue Biophysical Characterization and Molecular Engineering of Multidomain Proteins)

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