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We hypothesized that any Nef-SH3 domain interactions would be lost upon mutation of the prolines or arginine of PXXPXR. Further, mutation of the non-motif \u201cX\u201d residues, (Q73, V74, and L75) would give altered patterns of inhibition for different Nef\/SH3 domain protein interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that mutations of either of the prolines or the arginine of PXXPXR are defective for Nef-Hck binding, Nef\/activated PAK2 complex formation and enhancement of virion infectivity (EVI). Mutation of the non-motif \u201cX\u201d residues (Q, V and L) gave similar patterns of inhibition for Nef\/activated PAK2 complex formation and EVI which were distinct from the pattern for Hck binding. These results implicate an SH3 domain containing protein other than Hck for Nef\/activated PAK2 complex formation and EVI. We have also mutated Nef residues at the N-and C-terminal ends of the polyproline segment to explore interactions outside of PXXPXR. We discovered a new locus GFP\/F (G<jats:sub>67<\/jats:sub>, F<jats:sub>68<\/jats:sub>, P<jats:sub>69<\/jats:sub>and F<jats:sub>90<\/jats:sub>) that is required for Nef\/activated PAK2 complex formation and EVI.<\/jats:p><jats:p>MHC Class I (MHCI) downregulation was only partially inhibited by mutating the PXXPXR motif residues, but was fully inhibited by mutating the C-terminal P<jats:sub>78<\/jats:sub>. Further, we observed that MHCI downregulation strictly requires G<jats:sub>67<\/jats:sub>and F<jats:sub>68<\/jats:sub>. Our mutational analysis confirms the recently reported structure of the complex between Nef, AP-1 \u03bc1 and the cytoplasmic tail of MHCI, but does not support involvement of an SH3 domain protein in MHCI downregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Nef has evolved to be dependent on interactions with multiple SH3 domain proteins. To the N- and C- terminal sides of the polyproline helix are multifunctional protein interaction sites. The polyproline segment is also adapted to downregulate MHCI with a non-canonical binding surface. Our results demonstrate that Nef polyproline helix is highly adapted to directly interact with multiple host cell proteins.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1742-4690-9-47","type":"journal-article","created":{"date-parts":[[2012,7,19]],"date-time":"2012-07-19T18:30:23Z","timestamp":1342722623000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Overlapping effector interfaces define the multiple functions of the HIV-1 Nef polyproline helix"],"prefix":"10.1186","volume":"9","author":[{"given":"Lillian S","family":"Kuo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura L","family":"Baugh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah J","family":"Denial","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L","family":"Watkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J Victor","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L","family":"Foster","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2012,5,31]]},"reference":[{"key":"2873_CR1","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.virol.2006.03.044","volume":"351","author":"OT Fackler","year":"2006","unstructured":"Fackler OT, Moris A, Tibroni N, Giese SI, Glass B, Schwartz O, Krausslich HG: Functional characterization of HIV-1 Nef mutants in the context of viral infection. 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