Helical and β-Turn Conformations in the Peptide Recognition Regions of the VIM1 PHD Finger Abrogate H3K4 Peptide Recognition

The armadillo repeat serves as a scaffold for the development of modular peptide-recognition modules. In order to develop such a system, three crystal structures of designed armadillo-repeat proteins with third-generation N-caps (YIII-type), four or five internal repeats (M-type) and second-generation C-caps (AII-type) were determined at 1.8 Å (His-YIIIM4AII), 2.0 Å (His-YIIIM5AII) and 1.95 Å (YIIIM5AII) resolution and compared with those of variants with third-generation C-caps. All constructs are full consensus designs in which the internal repeats have exactly the same sequence, and hence identical conformations of the internal repeats are expected. The N-cap and internal repeats M1to M3are indeed extremely similar, but the comparison reveals structural differences in internal repeats M4and M5and the C-cap. These differences are caused by long-range effects of the C-cap, contacting molecules in the crystal, and the intrinsic design of the repeat. Unfortunately, the rigid-body movement of the C-terminal part impairs the regular arrangement of internal repeats that forms the putative peptide-binding site. The second-generation C-cap improves the packing of buried residues and thereby the stability of the protein. These considerations are useful for future improvements of an armadillo-repeat-based peptide-recognition system.

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Immunodominant-Peptide Recognition: Beta Testing TCRαβ

Immunity ◽

10.1016/j.immuni.2008.01.007 ◽

2008 ◽

Vol 28 (2) ◽

pp. 139-141 ◽

Cited By ~ 3

Author(s):

Jia-huai Wang ◽

Robert J. Mallis ◽

Ellis L. Reinherz

Keyword(s):

Peptide Recognition ◽

Beta Testing

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Deciphering and engineering chromodomain-methyllysine peptide recognition

Science Advances ◽

10.1126/sciadv.aau1447 ◽

2018 ◽

Vol 4 (11) ◽

pp. eaau1447 ◽

Cited By ~ 3

Author(s):

Ryan Hard ◽

Nan Li ◽

Wei He ◽

Brian Ross ◽

Gary C. H. Mo ◽

...

Keyword(s):

Protein Interactions ◽

Posttranslational Modifications ◽

Large Scale ◽

Regulation Of Gene Expression ◽

Live Cells ◽

Lysine Methylation ◽

Dynamic Regulation ◽

Peptide Recognition ◽

Protein Functions ◽

Domain Peptide

Posttranslational modifications (PTMs) play critical roles in regulating protein functions and mediating protein-protein interactions. An important PTM is lysine methylation that orchestrates chromatin modifications and regulates functions of non-histone proteins. Methyllysine peptides are bound by modular domains, of which chromodomains are representative. Here, we conducted the first large-scale study of chromodomains in the human proteome interacting with both histone and non-histone methyllysine peptides. We observed significant degenerate binding between chromodomains and histone peptides, i.e., different histone sites can be recognized by the same set of chromodomains, and different chromodomains can share similar binding profiles to individual histone sites. Such degenerate binding is not dictated by amino acid sequence or PTM motif but rather rooted in the physiochemical properties defined by the PTMs on the histone peptides. This molecular mechanism is confirmed by the accurate prediction of the binding specificity using a computational model that captures the structural and energetic patterns of the domain-peptide interaction. To further illustrate the power and accuracy of our model, we used it to effectively engineer an exceptionally strong H3K9me3-binding chromodomain and to label H3K9me3 in live cells. This study presents a systematic approach to deciphering domain-peptide recognition and reveals a general principle by which histone modifications are interpreted by reader proteins, leading to dynamic regulation of gene expression and other biological processes.

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