The Importance of Protein Dynamics for function and its relevance to Antigen Processing and Presentation

Editors

Tim Elliott

University of Oxford

Joern Martin Werner

University of Southampton

Impact

Ribbon and surface representations of ERAP1, ERAP2, and IRAP as revealed from the recent crystallographic studies. (A,B) ERAP1 complexes with the aminopeptidase inhibitor, bestatin, in the “closed” and “open” states, (C) ERAP2 and (D) IRAP complexes with a phosphinic pseudopeptidic inhibitor that is shown with orange colored spheres. For clarity, bestatin was omitted from the structures of ERAP1. The four domains are labeled and color-coded as cyan for domain I, blue for domain II, yellow for domain III, and red for domain IV. The catalytic zinc is shown as a pink sphere and the polymorphic site residues are indicated with green colored spheres. The modeled regions in ERAP1 that were not determined in the X-ray structures are shown in gray.

Mini Review

07 August 2017

The Role of Conformational Dynamics in Antigen Trimming by Intracellular Aminopeptidases

Athanasios Papakyriakou

and

Efstratios Stratikos

4,587 views

44 citations

Free energy landscapes and peptide tuning of the class I MHC (MHC-I) energy landscape. (A) Schematic showing the variation in protein-free energy with conformation. Atomic coordinates are along the x axis and free energy is along the y axis. Wells along the conformation axis represent different structural substates separated by barriers. The heights of the barriers yield the rates at which the protein moves between (or samples) different conformations. Low barriers translate into rapid, high-frequency motions, whereas high barriers translate into slower, low-frequency motions. The number and energy levels of the structural substates separated by the barriers gives the protein entropy. (B) Peptide tuning of the MHC-I energy landscape. Ligplot analysis (25) of the interactions the Tax and Flu M1 peptides make with HLA-A2. Peptides are shown with purple bonds and contacting MHC residues are indicated. Interactions formed by hydrophobic atoms are shown with red hashes. Hydrogen bonds are shown with green lines with distances indicated. HLA-A2 residues making significant interactions in one complex but not the other are circled in red. (C) Illustration of how peptides can tune the MHC-I energy landscape. The image shows a traditional folding funnel, with the native peptide/MHC-I architecture at the bottom of the funnel. Zooming into the tip of the funnel reveals the energy landscape of the assembled complex, as diagrammed in panel (A). Due to the different interactions formed by different peptides as shown in panel (B), the energy landscape is altered, changing MHC-I protein dynamics. Figure adapted from Ref. (26) and used by permission.

Mini Review

07 August 2017

Peptide and Peptide-Dependent Motions in MHC Proteins: Immunological Implications and Biophysical Underpinnings

Cory M. Ayres

, 1 more and

Brian M. Baker

8,165 views

43 citations

Diagrammatic representation of the major steps in the major histocompatibility complex (MHC) antigen presentation pathway that need to be included in a mechanistic model of viral peptide cell surface presentation. The measurable quantities required for such a model are mentioned in italics next to each step.

Perspective

10 July 2017

The Role of Multiscale Protein Dynamics in Antigen Presentation and T Lymphocyte Recognition

R. Charlotte Eccleston

, 2 more and

Peter V. Coveney

4,465 views

8 citations

Superimposition of crystal and modeled structures of major histocompatibility complex (MHC) molecules. The peptide of each MHC molecule is colored as indicated with the PDB accession code. The last three modeled structures were constructed in the study of Ref. (7). The figure is reprinted from Ref. (7).

Mini Review

29 May 2017

Exploration of the Conformational Dynamics of Major Histocompatibility Complex Molecules

Saeko Yanaka

and

Kenji Sugase

4,146 views

10 citations

Influence of peptide cargo on B*44:02 α3 fluctuations. Cα RMSF along sequence and the absolute difference compared to MHCIPL (|ΔPL|) are shown for each system. ΔRMSF are also mapped onto the structure of α3. Peptide not shown for clarity. (A) MHCIPD. (B) MHCIΔ1N–Δ3N. (C) MHCIΔ1C–Δ3C.

Original Research

18 April 2017

Partial Dissociation of Truncated Peptides Influences the Structural Dynamics of the MHCI Binding Groove

Olivier Fisette

, 1 more and

Lars V. Schäfer

3,634 views

22 citations

Expression of components of the major histocompatibility complex class II (MHCII) antigen presentation pathway across the stages of B cell development. Early B cells (pro-B, pre-B, and immature-B-cell) reside in the bone marrow. These stages are defined by the rearrangement of V, D, and J gene segments at the Ig heavy and light chain loci. At the pre-B cell stages, the pre-BCR is composed of a heavy chain paired with the surrogate light chain (λ 5-Vpre-B), together with signaling components Ig-α and Ig-β. The mature IgM-B cell receptor (BCR) emerges on immature B cells that exit the BM. They migrate to the spleen as transitional B cells and mature to naïve, pre-immune cells of the follicular (FO) B subset, found in the blood and secondary lymphoid organs. Upon immunological challenge, naïve FO B cells that successfully process and present MHCII-bound antigen to CD4+ T cells, differentiate into centroblasts and centrocytes organized in germinal centers. Following BCR affinity maturation, selected B cells further differentiate into long-lived memory B cells or antibody-secreting plasma cells. Relative expression of the MHCII antigen presentation machinery components is represented by color intensity.

Review

23 March 2017

The Other Function: Class II-Restricted Antigen Presentation by B Cells

Lital N. Adler

, 5 more and

Elizabeth D. Mellins

39,005 views

123 citations

Structural characteristics of major histocompatibility complex (MHC) class I and MHC class II proteins and their compartment-dependent loading with processed peptides. (A) Domain topology of a pMHC class I and pMHC class II complex. (B) Structure of HLA-A68 in complex with an HIV-derived peptide (PDB: 4HWZ, left) and HLA-DR1 in complex with a hemagglutinin-derived peptide (1DLH, right). Indicated are the supposed interaction sites of MHC class I with tapasin and of MHC class II with DM as dashed gray lines. The peptide is shown in yellow with its N and C-terminus marked and relevant pockets are labeled green (C) Simplified illustration of MHC class I (left) and II (right) processing and peptide-editing pathways. CLIP, class II-associated invariant chain peptide; Caln., calnexin; Calr., calreticulin; ER, endoplasmic reticulum; PLC, peptide loading complex.

Review

17 March 2017

Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation

Marek Wieczorek

, 5 more and

Christian Freund

593,360 views

788 citations

Model of the tapasin (Tsn)–major histocompatibility complex class I (MHC I) interaction. Cartoon representation of the predicted Tsn–MHC I complex, based on multi-microsecond all-atom MD simulations, for which the crystal structures of the lumenal portions of Tsn and HLA-B*44:02 were used as starting models (40, 55). There are two distinct interfaces, one between the N-terminal (distal) domain of Tsn and the α2-1-helix region of the MHC I heavy chain (MHC I hc) (A), the other between the membrane-proximal domain of Tsn and the α3 domain of the MHC I hc (B). Residues predicted to be part of the interfaces are shown as sticks in the close-up views. β2m, β2-microglobulin.

Review

08 February 2017

Proofreading of Peptide—MHC Complexes through Dynamic Multivalent Interactions

Christoph Thomas

and

Robert Tampé

8,657 views

49 citations

Review

30 January 2017

Structure and Dynamics of Antigenic Peptides in Complex with TAP

Elisa Lehnert

and

Robert Tampé

9,723 views

35 citations

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