NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation.
Proc Natl Acad Sci U S A. 2010 Dec 14;
Authors: Metcalf DG, Moore DT, Wu Y, Kielec JM, Molnar K, Valentine KG, Wand AJ, Bennett JS, Degrado WF
The integrin ?IIb?3 is a transmembrane (TM) heterodimeric adhesion receptor that exists in equilibrium between resting and active ligand binding conformations. In resting ?IIb?3, the TM and cytoplasmic domains of ?IIb and ?3 form a heterodimer that constrains ?IIb?3 in its resting conformation. To study the structure and dynamics of the cytoplasmic domain heterodimer, we prepared a disulfide-stabilized complex consisting of portions of the TM domains and the full cytoplasmic domains. NMR and hydrogen-deuterium exchange of this complex in micelles showed that the ?IIb cytoplasmic domain is largely disordered, but it interacts with and influences the conformation of the ?3 cytoplasmic domain. The ?3 cytoplasmic domain consists of a stable proximal helix contiguous with the TM helix and two distal amphiphilic helices. To confirm the NMR structure in a membrane-like environment, we studied the ?3 cytoplasmic domain tethered to phospholipid bilayers. Hydrogen-deuterium exchange mass spectrometry, as well as circular dichroism spectroscopy, demonstrated that the ?3 cytoplasmic domain becomes more ordered and helical under these conditions, consistent with our NMR results. Further, these experiments suggest that the two distal helices associate with lipid bilayers but undergo fluctuations that would allow rapid binding of cytoplasmic proteins regulating integrin activation, such as talin and kindlin-3. Thus, these results provide a framework for understanding the kinetics and thermodynamics of protein interactions involving integrin cytoplasmic domains and suggest that such interactions act in a concerted fashion to influence integrin stalk separation and exposure of extracellular ligand binding sites.
PMID: 21156831 [PubMed - as supplied by publisher]
NMR analysis of the αIIbβ3 cytoplasmic interaction suggests a mechanism for integrin regulation [Biochemistry]
NMR analysis of the αIIbβ3 cytoplasmic interaction suggests a mechanism for integrin regulation
Metcalf, D. G., Moore, D. T., Wu, Y., Kielec, J. M., Molnar, K., Valentine, K. G., Wand, A. J., Bennett, J. S., DeGrado, W. F....
Date: 2010-12-28
The integrin ?IIb?3 is a transmembrane (TM) heterodimeric adhesion receptor that exists in equilibrium between resting and active ligand binding conformations. In resting ?IIb?3, the TM and cytoplasmic domains of ?IIb and ?3 form a heterodimer that constrains ?IIb?3 in its resting conformation. To study the structure and dynamics of...
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01-03-2011 10:48 PM
NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation [Biochemistry]
NMR analysis of the {alpha}IIb{beta}3 cytoplasmic interaction suggests a mechanism for integrin regulation
Metcalf, D. G., Moore, D. T., Wu, Y., Kielec, J. M., Molnar, K., Valentine, K. G., Wand, A. J., Bennett, J. S., DeGrado, W. F....
Date: 2010-12-28
The integrin IIbβ3 is a transmembrane (TM) heterodimeric adhesion receptor that exists in equilibrium between resting and active ligand binding conformations. In resting IIbβ3, the TM and cytoplasmic domains of IIb and β3 form a heterodimer that constrains IIbβ3 in its resting conformation. To study the structure...
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12-29-2010 06:01 AM
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12-01-2010 06:56 PM
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11-19-2010 08:44 PM
[NMR paper] Novel mechanism of regulation of the non-receptor protein tyrosine kinase Csk: insigh
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11-19-2010 08:44 PM
[NMR paper] NMR analysis of structure and dynamics of the cytosolic tails of integrin alpha IIb b
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Biochemistry. 2001 Jun 26;40(25):7498-508
Authors: Ulmer TS, Yaspan B, Ginsberg MH, Campbell ID
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11-19-2010 08:32 PM
[NMR paper] alpha-->beta transition of beta-lactoglobulin as evidenced by heteronuclear NMR.
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J Mol Biol. 1998 Nov 6;283(4):731-9
Authors: Kuwata K, Hoshino M, Era S, Batt CA, Goto Y
Whereas bovine beta-lactoglobulin is a predominantly beta-sheet protein, it has a marked alpha-helical preference and can be considered to be a useful model of the alpha-->beta transition, a key issue for understanding the folding and biological function of a number of proteins....
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11-17-2010 11:15 PM
[NMR paper] 19F and 31P NMR spectroscopy of G protein alpha subunits. Mechanism of activation by
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J Biol Chem. 1991 Feb 25;266(6):3396-401
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