Protein adsorption on tailored substrates: long-range forces and conformational changes

2008 ◽  
Vol 20 (40) ◽  
pp. 404226 ◽  
Author(s):  
M Bellion ◽  
L Santen ◽  
H Mantz ◽  
H Hähl ◽  
A Quinn ◽  
...  
Keyword(s):  
Protein Adsorption ◽  
Long Range ◽  
Conformational Changes

scholarly journals FcαRI binding at the IgA1 CH2–CH3 interface induces long-range conformational changes that are transmitted to the hinge region

2018 ◽  
Vol 115 (38) ◽  
pp. E8882-E8891 ◽  
Author(s):  
Monica T. Posgai ◽  
Sam Tonddast-Navaei ◽  
Manori Jayasinghe ◽  
George M. Ibrahim ◽  
George Stan ◽  
...  
Keyword(s):  
Binding Site ◽  
Long Range ◽  
Conformational Changes ◽  
Lectin Binding ◽  
Coarse Grained ◽  
Alanine Scanning Mutagenesis ◽  
Long Distance ◽  
Receptor Binding Site ◽  
Binding Interface ◽  
Functional Dynamics

IgA effector functions include proinflammatory immune responses triggered upon clustering of the IgA-specific receptor, FcαRI, by IgA immune complexes. FcαRI binds to the IgA1–Fc domain (Fcα) at the CH2–CH3 junction and, except for CH2 L257 and L258, all side-chain contacts are contributed by the CH3 domain. In this study, we used experimental and computational approaches to elucidate energetic and conformational aspects of FcαRI binding to IgA. The energetic contribution of each IgA residue in the binding interface was assessed by alanine-scanning mutagenesis and equilibrium surface plasmon resonance (SPR). As expected, hydrophobic residues central to the binding site have strong energetic contributions to the FcαRI:Fcα interaction. Surprisingly, individual mutation of CH2 residues L257 and L258, found at the periphery of the FcαRI binding site, dramatically reduced binding affinity. Comparison of antibody:receptor complexes involving IgA or its precursor IgY revealed a conserved receptor binding site at the CH2–CH3 junction (or its equivalent). Given the importance of residues near the CH2–CH3 junction, we used coarse-grained Langevin dynamics simulations to understand the functional dynamics in Fcα. Our simulations indicate that FcαRI binding, either in an asymmetric (1:1) or symmetric (2:1) complex with Fcα, propagated long-range conformational changes across the Fc domains, potentially impacting the hinge and Fab regions. Subsequent SPR experiments confirmed that FcαRI binding to the Fcα CH2–CH3 junction altered the kinetics of HAA lectin binding at the IgA1 hinge. Receptor-induced long-distance conformational transitions have important implications for the interaction of aberrantly glycosylated IgA1 with anti-glycan autoantibodies in IgA nephropathy.

scholarly journals 3′-Azido-3′-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes

1998 ◽  
Vol 95 (16) ◽  
pp. 9518-9523 ◽  
Author(s):  
Jingshan Ren ◽  
Robert M. Esnouf ◽  
Andrew L. Hopkins ◽  
E. Yvonne Jones ◽  
Ian Kirby ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Long Range ◽  
Conformational Changes ◽  
Active Site ◽  
Common Mechanism ◽  
Resistance Mutations ◽  
Hiv Reverse Transcriptase ◽  
Drug Resistance Mutations ◽  
Hiv Rt

HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. Many of these drugs [e.g., 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxyinosine (ddI)] are analogues of the nucleoside substrates used by the HIV RT. One of the main problems in anti-HIV therapy is the selection of a mutant virus with reduced drug sensitivity. Drug resistance in HIV is generated for nucleoside analogue inhibitors by mutations in HIV RT. However, most of these mutations are situated some distance from the polymerase active site, giving rise to questions concerning the mechanism of resistance. To understand the possible structural bases for this, the crystal structures of AZT- and ddI-resistant RTs have been determined. For the ddI-resistant RT with a mutation at residue 74, no significant conformational changes were observed for the p66 subunit. In contrast, for the AZT-resistant RT (RTMC) bearing four mutations, two of these (at 215 and 219) give rise to a conformational change that propagates to the active site aspartate residues. Thus, these drug resistance mutations produce an effect at the RT polymerase site mediated simply by the protein. It is likely that such long-range effects could represent a common mechanism for generating drug resistance in other systems.

scholarly journals Designing allostery-inspired response in mechanical networks

2017 ◽  
Vol 114 (10) ◽  
pp. 2520-2525 ◽  
Author(s):  
Jason W. Rocks ◽  
Nidhi Pashine ◽  
Irmgard Bischofberger ◽  
Carl P. Goodrich ◽  
Andrea J. Liu ◽  
...  
Keyword(s):  
Long Range ◽  
Conformational Changes ◽  
Biological Molecules ◽  
Small Subset ◽  
Individual Response ◽  
Computationally Efficient ◽  
Mechanical Responses ◽  
Mechanical Networks ◽  
Disordered Networks ◽  
2D And 3D

Recent advances in designing metamaterials have demonstrated that global mechanical properties of disordered spring networks can be tuned by selectively modifying only a small subset of bonds. Here, using a computationally efficient approach, we extend this idea to tune more general properties of networks. With nearly complete success, we are able to produce a strain between any two target nodes in a network in response to an applied source strain on any other pair of nodes by removing only ∼1% of the bonds. We are also able to control multiple pairs of target nodes, each with a different individual response, from a single source, and to tune multiple independent source/target responses simultaneously into a network. We have fabricated physical networks in macroscopic 2D and 3D systems that exhibit these responses. This work is inspired by the long-range coupled conformational changes that constitute allosteric function in proteins. The fact that allostery is a common means for regulation in biological molecules suggests that it is a relatively easy property to develop through evolution. In analogy, our results show that long-range coupled mechanical responses are similarly easy to achieve in disordered networks.

Control and Characterization of Protein Adsorption on Ceramic Surfaces

1999 ◽  
Vol 599 ◽  
Author(s):  
M. J. Read ◽  
S. L. Burkett ◽  
A. M. Mayes
Keyword(s):  
Protein Adsorption ◽  
Conformational Changes ◽  
Surface Composition ◽  
Biological Properties ◽  
Protein Layer ◽  
Adsorption Mechanisms ◽  
Adsorbed Protein ◽  
Ceramic Surfaces ◽  
Model Protein

AbstractProtein adsorption to ceramic surfaces is an important early step in the function of implants. The types and amounts of adsorbed protein and the resulting conformational changes could mediate subsequent cell adhesion and inorganic deposition. Microporous silicoalumino-phosphates, which allow variations in surface composition within the same crystal structure, have been used as model surfaces. Effects of surface composition on adsorption isotherms, elutability, and biological activity of the adsorbed protein layer have been studied using lysozyme, a model protein. Control over protein adsorption mechanisms using well-characterized surface properties could be used to predict the biological properties of surfaces, and engineer coatings for a desired response.

scholarly journals Long Range Effect of Mutations on Specific Conformational Changes in the Extracellular Loop 2 of Angiotensin II Type 1 Receptor

2012 ◽  
Vol 288 (1) ◽  
pp. 540-551 ◽  
Author(s):  
Hamiyet Unal ◽  
Rajaganapathi Jagannathan ◽  
Anushree Bhatnagar ◽  
Kalyan Tirupula ◽  
Russell Desnoyer ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Long Range ◽  
Conformational Changes ◽  
Extracellular Loop ◽  
Range Effect ◽  
Loop 2

scholarly journals Long-Range Conformational Changes in Monoclonal Antibodies Revealed Using FPOP-LC-MS/MS

2019 ◽  
Vol 91 (23) ◽  
pp. 15163-15170 ◽  
Author(s):  
Owen Cornwell ◽  
Nicholas J. Bond ◽  
Sheena E. Radford ◽  
Alison E. Ashcroft
Keyword(s):  
Monoclonal Antibodies ◽  
Long Range ◽  
Conformational Changes

scholarly journals Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element

2014 ◽  
Vol 212 (1) ◽  
pp. 107-120 ◽  
Author(s):  
Kinjal Majumder ◽  
Olivia I. Koues ◽  
Elizabeth A.W. Chan ◽  
Katherine E. Kyle ◽  
Julie E. Horowitz ◽  
...  
Keyword(s):  
Long Range ◽  
Conformational Changes ◽  
Three Dimensional ◽  
Chromatin Conformation ◽  
Dynamic Changes ◽  
Architectural Elements ◽  
Receptor Locus ◽  
Long Range Interactions ◽  
Enhancer Function ◽  
Flanking Regions

Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unknown. We identify a novel mechanism by which cis-elements promote long-range interactions, inducing conformational changes critical for diversification of the TCRβ antigen receptor locus (Tcrb). Association between distal Vβ gene segments and the highly expressed DβJβ clusters, termed the recombination center (RC), is independent of enhancer function and recruitment of V(D)J recombinase. Instead, we find that tissue-specific folding of Tcrb relies on two distinct architectural elements located upstream of the RC. The first, a CTCF-containing element, directly tethers distal portions of the Vβ array to the RC. The second element is a chromatin barrier that protects the tether from hyperactive RC chromatin. When the second element is removed, active RC chromatin spreads upstream, forcing the tether to serve as a new barrier. Acquisition of barrier function by the CTCF element disrupts contacts between distal Vβ gene segments and significantly alters Tcrb repertoires. Our findings reveal a separation of function for RC-flanking regions, in which anchors for long-range recombination must be cordoned off from hyperactive RC landscapes by chromatin barriers.

scholarly journals Cryo-EM reveals local and global structural rearrangements in RYR mutants

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Kavita A. Iyer ◽  
Yifan Hu ◽  
Thomas Klose ◽  
Takashi Murayama ◽  
Montserrat Samsó
Keyword(s):  
Long Range ◽  
Conformational Changes ◽  
Large Scale ◽  
Single Point ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Point Mutations ◽  
Polymorphic Ventricular Tachycardia ◽  
Functional Studies ◽  
Single Point Mutations

Single-point mutations in ryanodine receptors (RYRs), large intracellular Ca2+ channels that play a critical role in EC coupling, are linked to debilitating and lethal disorders such as central core disease, malignant hyperthermia (for the skeletal isoform, RYR1), catecholaminergic polymorphic ventricular tachycardia, and ARVD2 (for the cardiac isoform, RYR2). Mutant RYRs result in elevated [Ca2+]cyto due to steady leak from the sarcoplasmic reticulum. To explore the nature of long-range allosteric mechanisms of malfunction, we determined the structure of two N-terminal domain mutants of RYR1, situated far away from the pore. Cryo-electron microscopy of the N-terminal subdomain A (NTDA) and subdomain C (NTDC) full-length mutants, RYR1 R163C (determined to 3.5 Å resolution), and RYR1 Y522S (determined to 4.0 Å resolution), respectively, reveal large-scale conformational changes in the cytoplasmic assembly under closed-state conditions (i.e., absence of activating Ca2+). The multidomain changes suggest that the mutations induce a preactivated state of the channel in R164C by altering the NTDA+/CD interface, and in Y522S by rearrangement of the α-helical bundle in NTDC. However, the extent of preactivation is considerably higher in Y522S as compared with R163C, which agrees with the increased severity of the Y522S mutation as established by various functional studies. The Y522S mutation represents loss of a spacer residue that is crucial for maintaining optimal orientation of α helices in NTDC, alteration of which has long-range effects felt as far away as ∼100 Å. Additionally, the structure of the Y522S mutant channel under open-state conditions also differs from RYR1 WT open channels. Our developing work with RYR mutants exhibits the diverse mechanisms by which these single-point mutations exert an effect on the channel’s function and highlight the complexity of the multidomain channel, as well as the need for targeted therapies.

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