Transmembrane Domain Helix Packing Stabilizes Integrin αIIbβ3 in the Low Affinity State*
By A. Partridge, Shouchun Liu, Sanguk Kim, J. Bowie, M. Ginsberg. Journal of Biological Chemistry, 2005
136 citations recorded by the source corpus.
Regulated changes in the affinity of integrin adhesion receptors (“activation”) play an important role in numerous biological functions including hemostasis, the immune response, and cell migration. Physiological integrin activation is the result of conformational changes in the extracellular domain initiated by the binding of cytoplasmic proteins to integrin cytoplasmic domains. The conformational changes in the extracellular domain are likely caused by disruption of intersubunit interactions between the α and β transmembrane (TM) and cytoplasmic domains. Here, we reasoned that mutation of residues contributing to α/β interactions that stabilize the low affinity state should lead to integrin activation. Thus, we subjected the entire intracellular domain of the β3 integrin subunit to unbiased random mutagenesis and selected it for activated mutants. 25 unique activating mutations were identified in the TM and membrane-proximal cytoplasmic domain. In contrast, no activating mutations were identified in the more distal cytoplasmic tail, suggesting that this region is dispensable for the maintenance of the inactive state. Among the 13 novel TM domain mutations that lead to integrin activation were several informative point mutations that, in combination with computational modeling, suggested the existence of a specific TM helix-helix packing interface that maintains the low affinity state. The interactions predicted by the model were used to identify additional activating mutations in both the α and β TM domains. Therefore, we propose that helical packing of the α and β TM domains forms a clasp that regulates integrin activation.
Subfields: Immunology and Allergy, Molecular Biology, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/15e534318c52a772b32ed51e1e390609231a620d
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In Immunology and Allergy
In Molecular Biology
In Radiology, Nuclear Medicine and Imaging
Citations in the corpus
- Integrin structure, activation, and interactions. (2011, methodology): “Evidence for this includes experiments using EM (Adair and Yeager 2002), disulfide cross-linking (Luo et al. 2004), activating mutations (Partridge et al. 2005), and FRET 4 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004994 of labeled cytoplasmic tails (Kim et al. 2003).”
- Structural basis of integrin activation by talin. (2007, methodology): “Integrin activation was assessed using the antibody PAC1 and flow cytometry as previously described (Partridge et al., 2005).”
- Integrin Structure and Function (2010, background): “The net result is a change in the position of the TM helix, leading to a packing mismatch within the aIIbb3-TM helix, and separation or reorientation of the integrin tails (Luo et al. 2004, 2005, 2007; Yin et al. 2006; Loh et al. 1996; Li et al. 2003, 2004, 2005; Partridge et al. 2005).”