Structure of an integrin aIIbb3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation Export

@article{citeulike:6007106, abstract = {10.1073/pnas.0909589106 Heterodimeric integrin adhesion receptors regulate diverse biological processes including angiogenesis, thrombosis and wound healing. The transmembrane-cytoplasmic domains (TMCDs) of integrins play a critical role in controlling activation of these receptors via an inside-out signaling mechanism, but the precise structural basis remains elusive. Here, we present the solution structure of integrin \^{I}±IIb\^{I}²3 TMCD heterodimer, which reveals a right-handed coiled-coil conformation with 2 helices intertwined throughout the transmembrane region. The helices extend into the cytoplasm and form a clasp that differs significantly from a recently published \^{I}±IIb\^{I}²3 TMCD structure. We show that while a point mutation in the clasp interface modestly activates \^{I}±IIb\^{I}²3, additional mutations in the transmembrane interface have a synergistic effect, leading to extensive integrin activation. Detailed analyses and structural comparison with previous studies suggest that extensive integrin activation is a highly concerted conformational transition process, which involves transmembrane coiled-coil unwinding that is triggered by the membrane-mediated alteration and disengagement of the membrane-proximal clasp. Our results provide atomic insight into a type I transmembrane receptor heterocomplex and the mechanism of integrin inside-out transmembrane signaling.}, author = {Yang, Jun and Ma, Yan-Qing and Page, Richard C. and Misra, Saurav and Plow, Edward F. and Qin, Jun}, citeulike-article-id = {6007106}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0909589106}, citeulike-linkout-1 = {http://www.pnas.org/content/early/2009/09/30/0909589106.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/early/2009/09/30/0909589106.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19805198}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19805198}, day = {20}, doi = {10.1073/pnas.0909589106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {integrin}, month = {October}, number = {42}, pages = {17729--17734}, posted-at = {2009-10-25 13:37:29}, priority = {4}, title = {Structure of an integrin aIIbb3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation}, url = {http://dx.doi.org/10.1073/pnas.0909589106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:6007106 L3 - citeulike-article-id:6007106 N2 - 10.1073/pnas.0909589106 Heterodimeric integrin adhesion receptors regulate diverse biological processes including angiogenesis, thrombosis and wound healing. The transmembrane-cytoplasmic domains (TMCDs) of integrins play a critical role in controlling activation of these receptors via an inside-out signaling mechanism, but the precise structural basis remains elusive. Here, we present the solution structure of integrin αIIbβ3 TMCD heterodimer, which reveals a right-handed coiled-coil conformation with 2 helices intertwined throughout the transmembrane region. The helices extend into the cytoplasm and form a clasp that differs significantly from a recently published αIIbβ3 TMCD structure. We show that while a point mutation in the clasp interface modestly activates αIIbβ3, additional mutations in the transmembrane interface have a synergistic effect, leading to extensive integrin activation. Detailed analyses and structural comparison with previous studies suggest that extensive integrin activation is a highly concerted conformational transition process, which involves transmembrane coiled-coil unwinding that is triggered by the membrane-mediated alteration and disengagement of the membrane-proximal clasp. Our results provide atomic insight into a type I transmembrane receptor heterocomplex and the mechanism of integrin inside-out transmembrane signaling. IS - 42 JF - Proceedings of the National Academy of Sciences EP - 17734 TI - Structure of an integrin aIIbb3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation VL - 106 SP - 17729 KW - integrin AU - Yang, Jun AU - Ma, Yan-Qing AU - Page, Richard AU - Misra, Saurav AU - Plow, Edward AU - Qin, Jun PY - 2009/10/20/ UR - http://dx.doi.org/10.1073/pnas.0909589106 ER -