PDBsum entry: 1qqg

Signal transduction

PDB id: 1qqg

Contents

Protein chains

207 a.a. *

Waters ×168

* Residue conservation analysis

PDB id:

1qqg

Name:

Signal transduction

Title:

Crystal structure of the ph-ptb targeting region of irs-1

Structure:

Insulin receptor substrate 1. Chain: a, b. Fragment: ph-ptb (n-terminal domain). Synonym: irs-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: this sequence occurs naturally in humans.

Biol. unit:

Dimer (from PQS)

Resolution:

2.30Å R-factor: 0.191 R-free: 0.247

Authors:

S.Dhe-Paganon,S.E.Shoelson

Key ref:

S.Dhe-Paganon et al. (1999). Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-PTB) targeting region of insulin receptor substrate 1. Proc Natl Acad Sci U S A, 96, 8378-8383. PubMed id: 10411883 DOI: 10.1073/pnas.96.15.8378

Date:

04-Jun-99 Release date: 01-Aug-99

Protein chains

P35568  (IRS1_HUMAN) -  Insulin receptor substrate 1

Seq: 1242 a.a.

Struc: 207 a.a.

 Gene Ontology (GO) functional annotation 

• Biochemical function: insulin receptor binding (1 term)

DOI no: 10.1073/pnas.96.15.8378

Proc Natl Acad Sci U S A 96:8378-8383 (1999)

PubMed id: 10411883

Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-PTB) targeting region of insulin receptor substrate 1.

S.Dhe-Paganon, E.A.Ottinger, R.T.Nolte, M.J.Eck, S.E.Shoelson.

ABSTRACT

We have determined the crystal structure at 2.3-A resolution of an amino-terminal segment of human insulin receptor substrate 1 that encompasses its pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains. Both domains adopt the canonical seven-stranded beta-sandwich PH domain fold. The domains are closely associated, with a 720-A(2) contact surface buried between them that appears to be stabilized by ionic, hydrophobic, and hydrogen bonding interactions. The nonconserved 46-residue linker between the domains is disordered. The PTB domain peptide binding site is fully exposed on the molecular surface, as is a large cationic patch at the base of the PH domain that is a likely binding site for the head groups of phosphatidylinositol phosphates. Binding assays confirm that phosphatidylinositol phosphates bind the PH domain, but not the PTB domain. Ligand binding to the PH domain does not alter PTB domain interactions, and vice versa. The structural and accompanying functional data illustrate how the two binding domains might act cooperatively to effectively increase local insulin receptor substrate 1 concentration at the membrane and transiently fix the receptor and substrate, to allow multiple phosphorylation reactions to occur during each union.

Selected figure(s)

Figure 1.
Fig. 1. Sequence alignment of the amino-terminal domains of human IRS-1 and IRS-2 and rat IRS-3 and IRS-4. Secondary structural elements of IRS-1 are shown above the alignments, and colored green ( -sheets) or turquoise ( -helices). Residues of the PTB domain that bind IR are labeled with red (phosphate binding) or black (all others) squares (13). PH domain residues forming the cationic patch at its base are labeled with black squares. Residues that are buried at the interface between domains are identified either as contributing to the hydrophobic patch ( ) or as a specific interaction [e.g., the PH domain residue labeled a (Arg-75) forms a salt bridge with PTB domain residue a (Glu-162), etc.]. Note the high degree of residue conservation at the interface and the great variability in length and composition of the interdomains of the four proteins.

Figure 5.
Fig. 5. Model for insulin signaling through the IR/IRS axis. (A) Under basal conditions in the absence of insulin, IR (green) is not phosphorylated (TM, transmembrane domain; JM, juxtamembrane domain; IRK, IR kinase). IRS (blue) associates reversibly with PI(4,5)P[2] (red) in the plasma membrane. Phosphates are represented by the letter P within closed black circles. (B) Insulin stimulates IR activation, leading to phosphorylation of three Tyr residues in the activation loop of IRK and one in the JM NPXY motif. Membrane-bound IRS proteins associate with the receptor JM, which transiently fixes the two proteins for phosphorylation of multiple tyrosine residues in the IRS activation domain.

Figures were selected by an automated process.