5i22

Amphiphysin SH3 in complex with Chikungunya virus nsP3 peptide

spinqualitylabelsall models 5i22, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5i22 is a 2 chain structure with sequence from Chikv and Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: BIN1, AMPHL (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [BIN1_HUMAN] Defects in BIN1 are the cause of centronuclear myopathy type 2 (CNM2) [MIM:255200]. A congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. Function [BIN1_HUMAN] May be involved in regulation of synaptic vesicle endocytosis. May act as a tumor suppressor and inhibits malignant cell transformation. Publication Abstract from PubMed We show that a peptide from Chikungunya virus nsP3 protein spanning residues 1728-1744 binds the amphiphysin-2 (BIN1) Src homology-3 (SH3) domain with an unusually high affinity (Kd 24 nM). Our NMR solution complex structure together with ITC data on several related viral and cellular peptide ligands reveal that this exceptional affinity originates from interactions between multiple basic residues in the target peptide and the extensive negatively charged binding surface of amphiphysin-2 SH3. Remarkably, these arginines show no fixed conformation in the complex structure indicating that a transient or fluctuating polyelectrostatic interaction accounts for this affinity. Thus, via optimization of such dynamic electrostatic forces viral peptides have evolved a superior binding affinity for amphiphysin-2 SH3 compared to typical cellular ligands, such as dynamin, thereby enabling hijacking of amphiphysin-2 SH3 regulated host cell processes by these viruses. Moreover, our data show that the previously described consensus sequence PxRPxR for amphiphysin SH3 ligands is inaccurate, and instead define it as an extended Class II binding motif PxxPxRpxR, where additional positive charges between the two constant arginine residues can give rise to extraordinary high SH3 binding affinity. Structural Basis of the High-Affinity Interaction Between the Alphavirus Nonstructural Protein-3 (nsP3) and the SH3 Domain of Amphiphysin-2.,Tossavainen H, Aitio O, Hellman M, Saksela K, Permi P J Biol Chem. 2016 Jun 6. pii: jbc.M116.732412. PMID:27268056 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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