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What are integrins?
a. integrins are a family of membrane proteins found only in animals that play a key role in integrating the extracellular and intracellular envioronments
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What do integrins do on the outer side?
i. integrins bind to moelecuels that are present in the excellular environment
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What do integrins do on the intracellular side?
i. integrins interact either directly or indirectly with dozens of different proteins to influence the course of events within the cell
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a. integrins are composed of two membrane-spanning polypeptide chains, __,, that are __linked
How many of each
- an alpha chain and a beta chain
- noncovalently
- 18 alpha and 8 beta
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1. more than __ possible pairings could occur, but only about __ have been identified, each with a specific distribution within the body
a. whereas many subunits occur in only a single __, the __is found in 12 different integrins and the __ in 5 of them
- 100
- 2 dozen
- integrin heretodimer
- beta-1 subunit
- alpha-v subunit
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i. most cells possess a variety of different __, and conversely, most __are present on a variety of different cell types
integrins x2
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How are the two subunits oriented?
- i. so as to form a globular extracellular head connected to the membrane by a pair of elongated “legs”
- 1. the legs of each subunit extend through the lipid bilayer as a single transmembrane helix and end in a small cytoplasmic domain of about 20-70 amino acids
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i. many integrins can exist on the surface of a cell in an __
1. these can be activated rapidly by events within the cell that alter the conformation of the __ of the integrin’s subnunits
- inactive conformation
- cytoplasmic domains
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1. changes in conformation of the __ are propagated through the molecule, increasing the integrin’s affinity for an extracellular ligand
a. ex: aggregation of platelets during blood clotting occurs only after the cytoplasmic activation of alpha-IIb-beta-3 integrins, which increases their affinity for fibrinogen
cytoplasmic domains
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i. this type of alteration in integrin affinity triggered by changes occurring inside the cell is __ signaling
1. in its absence, the integrin remains in the __, which protects the body against the formation of an inappropriate blood clot
- "inside-out"
- inactive state
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i. the __ of an integrin corresponds to the __state of the protein, one that is incapable of __
1. when bound to something, the integrin is not __ but __
a. ligand bound to the head of the integrin in a cleft where the __ come together
- bent conformation
- inactive
- binding a ligand
- bent
- upright
- alpha and beta subunits
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i. if the bent and upright structures represent the inactive and active states of an integrin, it is important to consider what type of __is capable of triggering such a remarkable transformation in protein conformation
stimulus
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1. in the bent, inactive conformation, the transmembrane domains of the two subunits are in __, apprarently held together by __ between residues of the __
a. the __ of integrins bind a wide array of proteins; one of these proteins is called __,
- close proximity
- noncovalent interactions
- two helices
- cytoplasmic domains
- talin
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What does talin do?
causes separation of the alpha and beta subunits
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i. mutations in __that block its interaction with __ also prevent __ and __ to the ECM
1. separation of the __ and __ of an integrin that results when __is bound is thought to send a change in conformation through the __, causing the molecule to assume an __position in which the head of the protein is capable o finteracting specifically with its appropriate ligand
- talin
- beta-integrin subunits
- activation of integrins and adhesion
- cytoplasmic tails and transmembrane domains
- talin
- legs of the integrin
- upright
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a. an increase in affinity of individual integrins is often followed by __ of the activated integrins, which enhances the overall __of the interaction between the cell surface and its extracellular ligands
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i. integrins have been implicated in two major types of activities
- 1. adhesion of cells to their substratum (or to other cells)
- 2. transmission of signals between the external environment and the cell interior
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Inside-out signaling affects?
binding properties of integrins
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a. signaling in the opposite direction, __, occurs when the binding of the __ of an integrin to a ligand can induce a conformational change at the __ of the integrin,e specially its __
- outside-in
- extracellular domain
- opposite, cytoplasmic end
- beta subunit
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i. changes at the cytoplasmic end can, in turn, alter __
1. ex: outside-in signals can induce a conformational change in __on the inside of the membrane, initiating a cascade of events leading to the polymerization of actin filaments of the cytoskeleton
- the way the integrin interacts with a host of different cytoplasmic proteins, modifying their activity
- talin
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1. also, binding of integrins to an EC ligand can trigger __, which create a __
- cytoplasmic protein kinases
- chain reaction
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i. __ transmitted by integrins (and other cell-surface molecules) can influence many aspects of cell behavior, including differentiation, motility, etc.
1. influence seen in malignant vs. normal cells
outside-in signals
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i. linkage between integrins and ligands mediates __between cells and their envirionment
1. because individual cells may express different __ on their cell surface, such cells are capable of binding to a variety of different extracellular components
a. most integrins have unique functions
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i. many EC proteins that bind to integrins do so because they have the amino acid sequence __
1. htis __is present in the cell-binding sites of __, __, __, and various other extracellular proteins
- argininie-glycine-aspartic acid
- tripeptide
- proteoglycans
- fibronectin
- laminin
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i. the discovery of the importance of the RGD sequence à new __
1. when wall of blood vessel is injured, the damaged region is sealed by the __
a. if occurring incorrectly, they can clotà heart attack or stroke
- treatments
- controlled aggregation of blood platelets
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i. aggregation requires __ to act as __to hold the platelets together
1. __ can inhibit blood clot formation by preventing the platelet integrin from binding to blood proteins
a. led to design of new class of __ that resemble RGD but bind only to __
- platelet-specific integrin
- linkers
- RGD-containing peptides
- antithrombotic agents
- platelet integrin
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i. __ of integrins contain binding sites for a variety of __, including several that act as adaptors that link the integrin to actin filaments of the cytoskeleton
1. the role of integrins in making the connection between the ECM and the cytoskeleton is best seen in two specialized structures: __ and __
- cytoplasmic domains
- cytoplasmic proteins
- focal adhesions and hemidesmosomes
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