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Titolo:
Single-amino acid substitutions alter the specificity and affinity of PDZ domains for their ligands
Autore:
Gee, SH; Quenneville, S; Lombardo, CR; Chabot, J;
Indirizzi:
Univ Ottawa, Neuromuscular Res Grp, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada Univ Ottawa Ottawa ON Canada K1H 8M5 Mol Med, Ottawa, ON K1H 8M5, Canada Burnham Inst, La Jolla, CA 92037 USA Burnham Inst La Jolla CA USA 92037Burnham Inst, La Jolla, CA 92037 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 47, volume: 39, anno: 2000,
pagine: 14638 - 14646
SICI:
0006-2960(20001128)39:47<14638:SASATS>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
DENSITY PROTEIN PSD-95; NITRIC-OXIDE SYNTHASE; SODIUM-CHANNELS; K+ CHANNELS; SYNTROPHIN; DYSTROPHIN; MEMBRANE; BINDING; RECOGNITION; RECEPTOR;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Gee, SH Univ Ottawa, Neuromuscular Res Grp, Dept Cellular & Mol Med, 451 Smyth Rd,Ottawa, ON K1H 8M5, Canada Univ Ottawa 451 Smyth Rd Ottawa ON Canada K1H 8M5 K1H 8M5, Canada
Citazione:
S.H. Gee et al., "Single-amino acid substitutions alter the specificity and affinity of PDZ domains for their ligands", BIOCHEM, 39(47), 2000, pp. 14638-14646

Abstract

PDZ domains are modular protein-protein interaction domains that bind to specific C-terminal sequences of membrane proteins and/or to other PDZ domains. Certain PDZ domains in PSD-95 and syntrophins interact with C-terminal peptide ligands and heterodimerize with the extended nNOS PDZ domain. The capacity to interact with nNOS correlates with the presence of a Lys residuein the carboxylate-binding loop of these PDZ domains. Here, we report thatsubstitution of an Arg for Lys-165 in PSD-95 PDZ2 disrupted its interaction with nNOS, but not with the C terminus of the Shaker-type K+ channel Kv1.4. The same mutation affected nNOS binding to alpha1- and beta1-syntrophin PDZ domains to a lesser extent, due in part to the stabilizing effect of tertiary interactions with the canonical nNOS PDZ domain. PDZ domains with anArg in the carboxylate-binding loop do not bind nNOS; however, substitution with Lys or Ala was able to confer nNOS binding. Our results indicate that the carboxylate-binding loop Lys or Arg is a critical determinant of nNOSbinding and that the identity of this residue can profoundly alter one mode of PDZ recognition without affecting another. We also analyzed the effects of mutating Asp-143, a residue in the alphaB helix of alpha1-syntrophin that forms a tertiary contact with the nNOS PDZ domain. This residue is important for both nNOS and C-terminal peptide binding and confers a preferencefor peptides with a positively charged residue at position -4. On this basis, we have identified the C terminus of the Kir2.1 channel as a possible binding partner for syntrophin PDZ domains. Together, our results demonstrate that single-amino acid substitutions alter the specificity and affinity of PDZ domains for their ligands.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/12/20 alle ore 22:25:09