Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatici+1–prolyli+2 amide bond: Implications for type VI β‐turn formation

Meng, Hai Yun; Thomas, Krista; Lee, Aaron E.; Zondlo, Neal J.

doi:10.1002/bip.20382

Cited by 47 publications

(72 citation statements)

References 143 publications

(209 reference statements)

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“…9C). Type VI ␤-turns are structural motifs uniquely conferred by cis prolines (57,58). The type VI ␤-turn also was stable over our triplicate 100-ns simulations of the inward-facing CFTR model.…”

Section: Discussionmentioning

confidence: 71%

Conserved Allosteric Hot Spots in the Transmembrane Domains of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels and Multidrug Resistance Protein (MRP) Pumps

Wei

Roessler

Chauvet

et al. 2014

Journal of Biological Chemistry

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Background: Multidrug resistance proteins (MRPs) and the cystic fibrosis transmembrane conductance regulator (CFTR) are thermodynamically distinct ATP-binding cassette (ABC) transporters. Results: Structural elements that couple ATP binding to channel opening in the CFTR channel also facilitate MRP drug export. Conclusion: MRPs and CFTR share components of a conserved activation mechanism. Significance: Allosteric hot spots suggest mechanistic similarities between thermodynamically distinct ABC transporters.

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Section: Discussionmentioning

confidence: 71%

Conserved Allosteric Hot Spots in the Transmembrane Domains of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels and Multidrug Resistance Protein (MRP) Pumps

Wei

Roessler

Chauvet

et al. 2014

Journal of Biological Chemistry

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“…S1). It is often (80%) followed by a bulky aromatic residue (Tyr or Phe) known to stabilize the proline cis isomer (33). This strong conservation is remarkable given an overall sequence identity of only 26% on average, and because cis prolines occur in less than 5% of the proteome (34).…”

Section: Discussionmentioning

confidence: 99%

Force-dependent isomerization kinetics of a highly conserved proline switch modulates the mechanosensing region of filamin

Rognoni

Möst

Žoldák

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Proline switches, controlled by cis-trans isomerization, have emerged as a particularly effective regulatory mechanism in a wide range of biological processes. In this study, we use single-molecule mechanical measurements to develop a full kinetic and energetic description of a highly conserved proline switch in the force-sensing domain 20 of human filamin and how prolyl isomerization modulates the force-sensing mechanism. Proline isomerization toggles domain 20 between two conformations. A stable cis conformation with slow unfolding, favoring the autoinhibited closed conformation of filamin's force-sensing domain pair 20-21, and a less stable, uninhibited conformation promoted by the trans form. The data provide detailed insight into the folding mechanisms that underpin the functionality of this binary switch and elucidate its remarkable efficiency in modulating force-sensing, thus combining two previously unconnected regulatory mechanisms, proline switches and mechanosensing. O wing to its ring structure (Fig. 1A), the peptidyl-prolyl bond is special among the peptide bonds in that it can populate slowly exchanging cis and trans conformations with similar probability (1). Therefore, proline residues can drastically affect the kinetics of folding (2, 3) as well as conformational changes of proteins (4, 5). Although most native protein conformations require trans prolines, there are a number of examples where native cis prolines have been reported (1,(6)(7)(8). In a few cases, both cis and trans conformations can be accommodated in the folded state thus leading to two distinct native states (9-11). Beyond its importance for protein folding, peptidyl-prolyl isomerization has also been discussed as a molecular timer switch regulating different functional conformations of proteins (5, 12).Filamins are essential actin cross-linkers as well as mechanosignaling hubs in the cytoskeleton. Recently, a special conformation in the rod 2 region of filamin has been shown to act as a force-sensing region mediating the interaction to transmembrane receptors like integrins or the von Willebrand receptor glycoprotein Ib (GPIb) (13-15) (Fig. 1B). Lad et al. (13) have shown that the first β-strand of domain 20 (FLNa20) of human filamin A binds to the subsequent domain 21 (FLNa21) thus covering and autoinhibiting its transmembrane receptor-binding site forming the domain pair shown in Fig. 1B. This domain pair has a mechanosensor function (15, 16). Mechanical force transmitted through the cytoskeleton leads to the opening of the domain pair and an increase in receptor-binding affinity of up to 17-fold (15). The crystal structure of FLNa20 exhibits a native cis proline just in front of the last β-strand (Fig. 1B, Inset). Interestingly, a multiple-sequence alignment shows that this cis proline residue is strictly conserved in all available 3D structures of filamin Ig-like domains (Fig. S1).Although proline isomerization has been investigated in numerous bulk studies, the structural heterogeneity caused by a native-state isomerization...

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“…Additionally, the clustering of aromatic and hydrophobic residues at the N-and Ctermini of the phage peptides presumably provides the driving force for β-hairpin folding (48). Our experimental data also indicate that the epitope is likely to be anchored by a type VI β-turn or touch turn, since the unusually high propensity for an aromatic residue to precede the central proline in the phage peptides is consistent with a cis-proline conformation (49)(50)(51). Additionally, the large decrease in 11-1F4 binding that occurred with the substitution of proline for alanine at position 8 of Len (1-18) is consistent with a cis-proline β-turn, as such a dramatic effect would not occur in β-turns anchored by a trans-prolyl residue (44,45).…”

Section: Confirmation Of the Structure Of The Neo-epitope Bound By 11mentioning

confidence: 65%

“…We attribute the stronger 11-1F4 interactions with κ4 fibrils, as compared with those formed from other LC isotypes (EC 50 s, 0.2 nM vs. ~ 100 nM, respectively (15)), to the presence of an Asp at position 9, given that the single germline gene that encodes V κ 4 proteins specifies this amino acid at this location (39); additionally, the Asp9 substitution in Len(1-18) resulted in a 60-fold weaker antibody binding with an EC 50 value similar to that for non-κ4 LCs. Further, ~60% of the 11-1F4-binding phage peptides contained a negatively charged amino acid (Asp or Glu) at position 9.…”

Section: Discussionmentioning

confidence: 99%

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Phage Display and Peptide Mapping of an Immunoglobulin Light Chain Fibril-Related Conformational Epitope

et al. 2007

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Amyloid fibrils and partially unfolded intermediates can be distinguished serologically from native amyloidogenic precursor proteins or peptides. In this regard, we previously had reported that mAb 11-1F4, generated by immunizing mice with a thermally denatured variable domain (V L ) fragment of the human κ4 Bence Jones protein Len, bound to a non-native conformational epitope located within the N-terminal 18 residues of fibrillar, as well as partially denatured, Ig light chains (O'Nuallain B. et al. (2006) Biochemistry 46, 1240. To define further the antibody binding site, we used random peptide phage display and epitope mapping of V L Len using wild-type and alaninemutated Len peptides where it was shown that the antibody epitope was reliant on up to 10 of the first 15 residues of protein Len. Comparison of V κ and V λ N-terminal germline consensus sequences with protein Len and 11-1F4-binding phages indicated that this antibody's cross-reactivity with light chains was related to an invariant proline at position(s) 7 and/or 8, bulky hydrophobic residues at positions 11 and 13, and additionally, to the ability to accommodate amino acid diversity at positions 1-4. Sequence alignments of the phage peptides revealed a central proline, often flanked by aromatic residues. Taken together, these results have provided evidence for the structural basis of the specificity of 11-1F4 for both κ and λ light chain fibrils. We posit that the associated binding site involves a rare type VI β-turn or touch-turn that is anchored by a cis-proline residue. The identification of an 11-1F4-related mimotope should facilitate development of pan-light chain fibril-reactive antibodies that could be used in the diagnosis and treatment of patients with AL amyloidosis.The amyloidoses are a group of over 20 protein misfolding disorders associated with often fatal sporadic and hereditary disorders, including Alzheimer's disease, type II diabetes, and primary (AL) amyloidosis (1-4). All types of amyloid, regardless of amino acid sequence, share tertiary structural and tinctorial features, i.e., they are formed from fibrils composed of extended β-sheets oriented perpendicularly to the long fibril axis (5,6) and bind the dyes thioflavin T and Congo red (7,8). Additionally, fibrils, as well as their assembly intermediates, contain generic conformational epitopes not present on the native proteins (9-16). These common characteristics reflect a similar fibrillogenic pathway(s) involving the assembly of soluble higher-order intermediates into fibrils that are structurally dissimilar to their precursors (2, 13,17).

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Effects of i and i+3 residue identity on Cis–Trans isomerism of the aromatic_i+1–prolyl_i+2 amide bond: Implications for type VI β‐turn formation

Cited by 47 publications

References 143 publications

Conserved Allosteric Hot Spots in the Transmembrane Domains of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels and Multidrug Resistance Protein (MRP) Pumps

Conserved Allosteric Hot Spots in the Transmembrane Domains of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels and Multidrug Resistance Protein (MRP) Pumps

Force-dependent isomerization kinetics of a highly conserved proline switch modulates the mechanosensing region of filamin

Phage Display and Peptide Mapping of an Immunoglobulin Light Chain Fibril-Related Conformational Epitope

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