6533b7d6fe1ef96bd1267192

RESEARCH PRODUCT

Structure of SNX9 SH3 in complex with a viral ligand reveals the molecular basis of its unique specificity for alanine-containing class I SH3 motifs

Helena TossavainenHasan UğurluMikael KarjalainenMaarit HellmanLina AntenucciRiku FagerlundKalle SakselaPerttu Permi

subject

DYNAMICSPROLINE-RICH PEPTIDESviruksetPROTEINSvirusesHTLV-1 GagLigandsEVOLUTIONARY CONSERVATIONalfaviruksetsrc Homology DomainsHIGH-AFFINITYretroviruksetDOMAINStructural BiologyBINDINGAnimalsHorsesMolecular Biologysoluviestintä11832 Microbiology and virologyAlanineBinding SitesPXXP MOTIFSisothermal titration calorimetrySH3solution NMR spectroscopyEEEV nsP3HIV-11182 Biochemistry cell and molecular biologyproteiinitCHEMICAL-SHIFTS3111 BiomedicinePeptidesSNX9Protein Binding

description

Class I SH3 domain-binding motifs generally comply with the consensus sequence [R/K]x0PxxP, the hydrophobic residue 0 being proline or leucine. We have studied the unusual 0 = Ala-specificity of SNX9 SH3 by determining its complex structure with a peptide present in eastern equine encephalitis virus (EEEV) nsP3. The structure revealed the length and composition of the n-Src loop as important factors determining specificity. We also compared the affinities of EEEV nsP3 peptide, its mutants, and cellular ligands to SNX9 SH3. These data suggest that nsP3 has evolved to minimize reduction of conformational entropy upon binding, hence acquiring stronger affinity, enabling takeover of SNX9. The RxAPxxP motif was also found in human T cell leukemia virus-1 (HTLV-1) Gag polyprotein. We found that this motif was required for efficient HTLV-1 infection, and that the specificity of SNX9 SH3 for the RxAPxxP core binding motif was importantly involved in this process. Peer reviewed

yearjournalcountryeditionlanguage
2021-08-12
10.1016/j.str.2022.03.006http://hdl.handle.net/10138/346308