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SH3-domain binding function of HIV-1 Nef is required for association with a PAK-related kinase

Manninen, A; Hiipakka, M; Vihinen, Mauno LU ; Lu, WG; Mayer, BJ and Saksela, K (1998) In Virology 250(2). p.273-282
Abstract
HIV-1 Nef has previously been shown to bind to Src homology-3 (SH3) domains of a subset of Src family tyrosine kinases. In addition, Nef has been reported to coprecipitate with a serine/threonine kinase activity termed NAK (for Nef-associated kinase). The identity of NAK remains uncertain, but it has been suggested to represent a novel member of the p21-activated kinase (PAK) family. We report here that NAK autophosphorylation is increased not only by an activated form of the p21-family GTPase cdc42 but also by a plasma membrane-targeted fragment of the adapter protein Nck, thus providing further evidence that NAK is related to PAKs. A detailed structure-based mutational analysis of Nef revealed that all amino acid changes that inhibited... (More)
HIV-1 Nef has previously been shown to bind to Src homology-3 (SH3) domains of a subset of Src family tyrosine kinases. In addition, Nef has been reported to coprecipitate with a serine/threonine kinase activity termed NAK (for Nef-associated kinase). The identity of NAK remains uncertain, but it has been suggested to represent a novel member of the p21-activated kinase (PAK) family. We report here that NAK autophosphorylation is increased not only by an activated form of the p21-family GTPase cdc42 but also by a plasma membrane-targeted fragment of the adapter protein Nck, thus providing further evidence that NAK is related to PAKs. A detailed structure-based mutational analysis of Nef revealed that all amino acid changes that inhibited the Nef/Hck-SH3 interaction, as measured by surface-plasmon resonance, also abolished coprecipitation of NAK. As PAK family proteins do not contain SH3 domains, these observations are best explained by a protein complex in which Nef, NAK, and an SH3-protein all contact each other. In addition, a number of conserved amino acids in Nef that are not involved in SH3 binding were also found to be crucial for association with NAK. Molecular modeling suggests that these residues are involved in formation of an adjacent binding surface for NAK or another critical component of the NAK/Nef complex. (C) 1998 Academic Press (Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
HIV, AIDS, Nef, SH3, PAK, NAK, cdc42, Hck, protein kinase
in
Virology
volume
250
issue
2
pages
273 - 282
publisher
Elsevier
external identifiers
  • wos:000076652100003
  • scopus:0032566903
ISSN
1096-0341
DOI
10.1006/viro.1998.9381
language
English
LU publication?
no
id
8e42d93f-2e99-482f-960d-abd1657b564b (old id 3852395)
date added to LUP
2013-06-28 13:43:44
date last changed
2017-01-01 06:40:06
@article{8e42d93f-2e99-482f-960d-abd1657b564b,
  abstract     = {HIV-1 Nef has previously been shown to bind to Src homology-3 (SH3) domains of a subset of Src family tyrosine kinases. In addition, Nef has been reported to coprecipitate with a serine/threonine kinase activity termed NAK (for Nef-associated kinase). The identity of NAK remains uncertain, but it has been suggested to represent a novel member of the p21-activated kinase (PAK) family. We report here that NAK autophosphorylation is increased not only by an activated form of the p21-family GTPase cdc42 but also by a plasma membrane-targeted fragment of the adapter protein Nck, thus providing further evidence that NAK is related to PAKs. A detailed structure-based mutational analysis of Nef revealed that all amino acid changes that inhibited the Nef/Hck-SH3 interaction, as measured by surface-plasmon resonance, also abolished coprecipitation of NAK. As PAK family proteins do not contain SH3 domains, these observations are best explained by a protein complex in which Nef, NAK, and an SH3-protein all contact each other. In addition, a number of conserved amino acids in Nef that are not involved in SH3 binding were also found to be crucial for association with NAK. Molecular modeling suggests that these residues are involved in formation of an adjacent binding surface for NAK or another critical component of the NAK/Nef complex. (C) 1998 Academic Press},
  author       = {Manninen, A and Hiipakka, M and Vihinen, Mauno and Lu, WG and Mayer, BJ and Saksela, K},
  issn         = {1096-0341},
  keyword      = {HIV,AIDS,Nef,SH3,PAK,NAK,cdc42,Hck,protein kinase},
  language     = {eng},
  number       = {2},
  pages        = {273--282},
  publisher    = {Elsevier},
  series       = {Virology},
  title        = {SH3-domain binding function of HIV-1 Nef is required for association with a PAK-related kinase},
  url          = {http://dx.doi.org/10.1006/viro.1998.9381},
  volume       = {250},
  year         = {1998},
}