5by9
From Proteopedia
The crystal structure of polyglycilated 14-3-3 protein from Giardia intestinalis
Structural highlights
Function1433_GIAIC Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner (By similarity). Binds with varying affinity to various synthetic phosphopeptides having a consensus binding motif RSX(pS/pT)XP, called mode-1, where X is any residue and pS/pT is a phosphorylated serine/threonine, and to synthetic phosphopeptides having a consensus binding motif Xp(S/T)X1-2-COOH, called mode-3, in which the phosphorylated residue occupies the penultimate C-terminal position in the target protein, but does not bind to their unphosphorylated counterparts (PubMed:19733174). Binds to synthetic human RAF1 phosphopeptides, but not to their unphosphorylated forms. Binds to difopein, a polypeptide containing a phosphorylation-independent binding motif (PubMed:16368691, PubMed:19733174). Involved in encystation (PubMed:19733174). Involved in cell proliferation. Required for actin and tubulin cytoskeletal organization. Regulates actin filament formation and nuclear size (PubMed:28932813).[UniProtKB:P62261][1] [2] [3] Publication Abstract from PubMedGiardiasis is a gastrointestinal diarrheal illness caused by the protozoan parasite Giardia duodenalis, which affects annually over 200 million people worldwide. The limited antigiardial drug arsenal and the emergence of clinical cases refractory to standard treatments dictate the need for new chemotherapeutics. The 14-3-3 family of regulatory proteins, extensively involved in protein-protein interactions (PPIs) with pSer/pThr clients, represents a highly promising target. Despite homology with human counterparts, the single 14-3-3 of G. duodenalis (g14-3-3) is characterized by a constitutive phosphorylation in a region critical for target binding, thus affecting the function and the conformation of g14-3-3/clients interaction. However, to approach the design of specific small molecule modulators of g14-3-3 PPIs, structural elucidations are required. Here, we present a detailed computational and crystallographic study exploring the implications of g14-3-3 phosphorylation on protein structure and target binding. Self-Guided Langevin Dynamics and classical molecular dynamics simulations show that phosphorylation affects locally and globally g14-3-3 conformation, inducing a structural rearrangement more suitable for target binding. Profitable features for g14-3-3/clients interaction were highlighted using a hydrophobicity-based descriptor to characterize g14-3-3 client peptides. Finally, the X-ray structure of g14-3-3 in complex with a mode-1 prototype phosphopeptide was solved and combined with structure-based simulations to identify molecular features relevant for clients binding to g14-3-3. The data presented herein provide a further and structural understanding of g14-3-3 features and set the basis for drug design studies. Molecular Dynamics Simulations and Structural Analysis of Giardia duodenalis 14-3-3 Protein-Protein Interactions.,Cau Y, Fiorillo A, Mori M, Ilari A, Botta M, Lalle M J Chem Inf Model. 2015 Dec 28;55(12):2611-22. doi: 10.1021/acs.jcim.5b00452. Epub, 2015 Nov 19. PMID:26551337[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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