The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics

Xu Liu; Tyson R Shepherd; Ann M Murray; Zhen Xu; Ernesto J Fuentes

doi:10.1016/j.str.2013.01.004

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The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics

Journal article

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Peer reviewed

The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics

Xu Liu, Tyson R Shepherd, Ann M Murray, Zhen Xu and Ernesto J Fuentes

Structure (London), Vol.21(3), pp.342-354

03/05/2013

DOI: 10.1016/j.str.2013.01.004

PMCID: PMC4086710

PMID: 23395182

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Abstract

PDZ (PSD-95/Dlg/ZO-1) domains are protein-protein interaction modules often regulated by ligand phosphorylation. Here, we investigated the specificity, structure, and dynamics of Tiam1 PDZ domain/ligand interactions. We show that the PDZ domain specifically binds syndecan1 (SDC1), phosphorylated SDC1 (pSDC1), and SDC3 but not other syndecan isoforms. The crystal structure of the PDZ/SDC1 complex indicates that syndecan affinity is derived from amino acids beyond the four C-terminal residues. Remarkably, the crystal structure of the PDZ/pSDC1 complex reveals a binding pocket that accommodates the phosphoryl group. Methyl relaxation experiments of PDZ/SCD1 and PDZ/pSDC1 complexes reveal that PDZ-phosphoryl interactions dampen dynamic motions in a distal region of the PDZ domain by decoupling them from the ligand-binding site. Our data are consistent with a selection model by which specificity and phosphorylation regulate PDZ/syndecan interactions and signaling events. Importantly, our relaxation data demonstrate that PDZ/phospho-ligand interactions regulate protein dynamics and their coupling to distal sites.

Amino Acid Sequence

Phosphorylation

Syndecan-3 - chemistry

Protein Structure, Secondary

Humans

Syndecan-2 - chemistry

Models, Molecular

Molecular Sequence Data

Crystallography, X-Ray

Structure-Activity Relationship

Syndecan-1 - chemistry

Computer Simulation

PDZ Domains

Protein Binding

Ligands

Binding Sites

T-Lymphoma Invasion and Metastasis-inducing Protein 1

Guanine Nucleotide Exchange Factors - chemistry

Syndecan-4 - chemistry

Details

Title: Subtitle: The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics
Creators: Xu Liu - Department of Biochemistry, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
Tyson R Shepherd
Ann M Murray
Zhen Xu
Ernesto J Fuentes
Resource Type: Journal article
Publication Details: Structure (London), Vol.21(3), pp.342-354
Publisher: United States
DOI: 10.1016/j.str.2013.01.004
PMID: 23395182
PMCID: PMC4086710
ISSN: 0969-2126
eISSN: 1878-4186
Grant note: GM067795 / NIGMS NIH HHS T32 GM067795 / NIGMS NIH HHS GM008365 / NIGMS NIH HHS T32 GM008365 / NIGMS NIH HHS
Language: English
Date published: 03/05/2013
Academic Unit: Biochemistry and Molecular Biology; Medicine Administration
Record Identifier: 9984024549602771

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