Dataset Information

Proteomic analysis of alpha4beta1 integrin adhesion complexes reveals alpha-subunit-dependent protein recruitment

ABSTRACT: Peptides and proteins identified for VCAM-1(D40A) control ligand affinity purification using K562-alpha4 cells (biological replicate 1)

INSTRUMENT(S): 4000 Q TRAP, instrument model

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Adam Byron

PROVIDER: PRD000565 | Pride | 2012-05-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	PRIDE_Exp_Complete_Ac_19284.pride.mgf.gz	Mgf
	PRIDE_Exp_Complete_Ac_19284.pride.mztab.gz	Mztab
	PRIDE_Exp_Complete_Ac_19284.xml.gz	Xml
	PRIDE_Exp_Complete_Ac_19285.pride.mgf.gz	Mgf
	PRIDE_Exp_Complete_Ac_19285.pride.mztab.gz	Mztab

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Proteomic analysis of α4β1 integrin adhesion complexes reveals α-subunit-dependent protein recruitment.

Byron Adam A Humphries Jonathan D JD Craig Sue E SE Knight David D Humphries Martin J MJ

Proteomics 20120701 13

Integrin adhesion receptors mediate cell-cell and cell-extracellular matrix interactions, which control cell morphology and migration, differentiation, and tissue integrity. Integrins recruit multimolecular adhesion complexes to their cytoplasmic domains, which provide structural and mechanosensitive signaling connections between the extracellular and intracellular milieux. The different functions of specific integrin heterodimers, such as α4β1 and α5β1, have been attributed to distinct signal t ...[more]

PMID: 22623428

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Project description:Integrin alpha(IIb)beta(3) plays a pivotal role in hemostasis and thrombosis by mediating adhesive interactions of platelets. Binding of alpha(IIb)beta(3) to its physiological ligands, immobilized fibrinogen and fibrin, induces outside-in signaling in platelets, leading to their adhesion and spreading even without prior stimulation by agonists. Implicit in these phenomena is a requirement for the linkage between integrins' cytoplasmic tails and intracellular proteins. However, the nature of the initiating signal has not been established. In this study, we examined whether binding of alpha(IIb)beta(3) to immobilized fibrin(ogen), per se, triggers interaction of the integrin with cytoplasmic proteins. Using the integrin-binding skelemin fragment as a marker of exposure of residues involved in the clasp between alpha(IIb) and beta(3) cytoplasmic tails, we showed that its binding site in the membrane-proximal beta(3) 715-730 segment is cryptic and becomes exposed as a result of binding of isolated alpha(IIb)beta(3) to immobilized ligands. Furthermore, the skelemin-like protein present in platelets and CHO cells does not associate with alpha(IIb)beta(3) in resting platelets or suspended alpha(IIb)beta(3)-expressing CHO cells but is recruited to integrin during cell adhesion. In addition, not only beta(3) but also the membrane-proximal 989-1000 segment of the alpha(IIb) cytoplasmic tail binds the skelemin fragment. Finally, the same residues, alpha(IIb) Val(990), alpha(IIb) Arg(995), and beta(3) His(722), involved in the formation of the clasp between the tails are also required for skelemin binding. These studies suggest that ligation of alpha(IIb)beta(3) by immobilized ligands during platelet adhesion induces a transmembrane conformation change in the integrin, resulting in unclasping of the complex between the membrane-proximal parts of cytoplasmic tails, thereby unmasking residues involved in binding the skelemin-like protein. Thus, the junction between alpha(IIb) and beta(3) cytoplasmic tails may contain the critical structural information for the initiation of outside-in signaling.