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Integrin activation and structural rearrangement

Among adhesion receptor families, integrins are particularly important in biological processes that require rapid modulation of adhesion and de‐adhesion. Activation on a timescale of

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Published in:	Immunological reviews 2002-08, Vol.186 (1), p.141-163
Main Authors:	Takagi, Junichi, Springer, Timothy A.
Format:	Article
Language:	English
Subjects:	Animals Cell Adhesion - immunology Humans Integrins - chemistry Integrins - immunology Ligands Protein Binding Protein Conformation Protein Structure, Tertiary Structure-Activity Relationship
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description	Among adhesion receptor families, integrins are particularly important in biological processes that require rapid modulation of adhesion and de‐adhesion. Activation on a timescale of
doi_str_mv	10.1034/j.1600-065X.2002.18613.x
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Activation on a timescale of < 1 s of β2 integrins on leukocytes and β3 integrins on platelets enables deposition of these cells at sites of inflammation or vessel wall injury. Recent crystal, nuclear magnetic resonance (NMR), and electron microscope (EM) structures of integrins and their domains lead to a unifying mechanism of activation for both integrins that contain and those that lack an inserted (I) domain. The I domain adopts two alternative conformations, termed open and closed. In striking similarity to signaling G‐proteins, rearrangement of a Mg2+‐binding site is linked to large conformational movements in distant backbone regions. Mutations that stabilize a particular conformation show that the open conformation has high affinity for ligand, whereas the closed conformation has low affinity. Movement of the C‐terminal α‐helix 10 Å down the side of the domain in the open conformation is sufficient to increase affinity at the distal ligand‐binding site 9000‐fold. This C‐terminal “bell‐rope” provides a mechanism for linkage to conformational movements in other domains. Recent structures and functional studies reveal interactions between β‐propeller, I, and I‐like domains in the integrin headpiece, and a critical role for integrin epidermal growth factor (EGF) domains in the stalk region. The headpiece of the integrin faces down towards the membrane in the inactive conformation, and extends upward in a “switchblade”‐like opening upon activation. 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Activation on a timescale of < 1 s of β2 integrins on leukocytes and β3 integrins on platelets enables deposition of these cells at sites of inflammation or vessel wall injury. Recent crystal, nuclear magnetic resonance (NMR), and electron microscope (EM) structures of integrins and their domains lead to a unifying mechanism of activation for both integrins that contain and those that lack an inserted (I) domain. The I domain adopts two alternative conformations, termed open and closed. In striking similarity to signaling G‐proteins, rearrangement of a Mg2+‐binding site is linked to large conformational movements in distant backbone regions. Mutations that stabilize a particular conformation show that the open conformation has high affinity for ligand, whereas the closed conformation has low affinity. Movement of the C‐terminal α‐helix 10 Å down the side of the domain in the open conformation is sufficient to increase affinity at the distal ligand‐binding site 9000‐fold. This C‐terminal “bell‐rope” provides a mechanism for linkage to conformational movements in other domains. Recent structures and functional studies reveal interactions between β‐propeller, I, and I‐like domains in the integrin headpiece, and a critical role for integrin epidermal growth factor (EGF) domains in the stalk region. The headpiece of the integrin faces down towards the membrane in the inactive conformation, and extends upward in a “switchblade”‐like opening upon activation. These long‐range structural rearrangements of the entire integrin molecule involving interdomain contacts appear closely linked to conformational changes within the I and I‐like domains, which result in increased affinity and competence for ligand binding.</description><subject>Animals</subject><subject>Cell Adhesion - immunology</subject><subject>Humans</subject><subject>Integrins - chemistry</subject><subject>Integrins - immunology</subject><subject>Ligands</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Structure, Tertiary</subject><subject>Structure-Activity Relationship</subject><issn>0105-2896</issn><issn>1600-065X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNqNkF1PwjAUhhujEUT_gtmVd5v9WLvtxkSJIgmoMSrGm6Yrp2a4DWw3hX_vBgQv9aqnOe_7NH0Q8ggOCGbh-SwgAmMfC_4aUIxpQGJBWLDcQ93dYh91McHcp3EiOujIuRnGJGI0PEQdQikLmUi6CA_LCt5tVnpKV9mXqrJ5M5ZTz1W21lVtVe5ZUNaq8h0KKKtjdGBU7uBke_bQ8831U__WH90Phv3Lka85F8zXqVBGhJrRKDKJSWnMFKhmB4ZRylOhp4CpEJxSrQngEHDCjVYmbG6EG9ZDZxvuws4_a3CVLDKnIc9VCfPayYiS5j-C_xls1fBEiCYYb4Lazp2zYOTCZoWyK0mwbLXKmWztydaebLWuu0wum-rp9o06LWD6W9x6bAIXm8B3lsPq32A5HD-uxwbgbwCZq2C5Ayj7IUXEIi4ndwM5TiZXL2H_Qb6xHyUzlhQ</recordid><startdate>200208</startdate><enddate>200208</enddate><creator>Takagi, Junichi</creator><creator>Springer, Timothy A.</creator><general>Munksgaard International Publishers</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>200208</creationdate><title>Integrin activation and structural rearrangement</title><author>Takagi, Junichi ; Springer, Timothy A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5563-cb6af64c3277f9fb283aeac55ef3225b6cde0266522cc1e04e095fcaf4c1e15f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Cell Adhesion - immunology</topic><topic>Humans</topic><topic>Integrins - chemistry</topic><topic>Integrins - immunology</topic><topic>Ligands</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protein Structure, Tertiary</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takagi, Junichi</creatorcontrib><creatorcontrib>Springer, Timothy A.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Immunological reviews</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takagi, Junichi</au><au>Springer, Timothy A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Integrin activation and structural rearrangement</atitle><jtitle>Immunological reviews</jtitle><addtitle>Immunol Rev</addtitle><date>2002-08</date><risdate>2002</risdate><volume>186</volume><issue>1</issue><spage>141</spage><epage>163</epage><pages>141-163</pages><issn>0105-2896</issn><eissn>1600-065X</eissn><abstract>Among adhesion receptor families, integrins are particularly important in biological processes that require rapid modulation of adhesion and de‐adhesion. Activation on a timescale of < 1 s of β2 integrins on leukocytes and β3 integrins on platelets enables deposition of these cells at sites of inflammation or vessel wall injury. Recent crystal, nuclear magnetic resonance (NMR), and electron microscope (EM) structures of integrins and their domains lead to a unifying mechanism of activation for both integrins that contain and those that lack an inserted (I) domain. The I domain adopts two alternative conformations, termed open and closed. In striking similarity to signaling G‐proteins, rearrangement of a Mg2+‐binding site is linked to large conformational movements in distant backbone regions. Mutations that stabilize a particular conformation show that the open conformation has high affinity for ligand, whereas the closed conformation has low affinity. Movement of the C‐terminal α‐helix 10 Å down the side of the domain in the open conformation is sufficient to increase affinity at the distal ligand‐binding site 9000‐fold. This C‐terminal “bell‐rope” provides a mechanism for linkage to conformational movements in other domains. Recent structures and functional studies reveal interactions between β‐propeller, I, and I‐like domains in the integrin headpiece, and a critical role for integrin epidermal growth factor (EGF) domains in the stalk region. The headpiece of the integrin faces down towards the membrane in the inactive conformation, and extends upward in a “switchblade”‐like opening upon activation. These long‐range structural rearrangements of the entire integrin molecule involving interdomain contacts appear closely linked to conformational changes within the I and I‐like domains, which result in increased affinity and competence for ligand binding.</abstract><cop>Oxford, UK</cop><pub>Munksgaard International Publishers</pub><pmid>12234369</pmid><doi>10.1034/j.1600-065X.2002.18613.x</doi><tpages>23</tpages></addata></record>
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subjects	Animals Cell Adhesion - immunology Humans Integrins - chemistry Integrins - immunology Ligands Protein Binding Protein Conformation Protein Structure, Tertiary Structure-Activity Relationship
title	Integrin activation and structural rearrangement
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