Integrins are a class of proteins found on the surface of cells, serving as connectors between a cell and its surrounding environment. They mediate interactions between cells and the extracellular matrix (ECM) or neighboring cells. This connection is fundamental for cellular processes like adhesion, movement, and sensing their surroundings.
Components and Arrangement
Integrins are not single proteins but rather functional units called heterodimers, composed of two different protein subunits: an alpha (α) subunit and a beta (β) subunit. These two subunits are noncovalently associated, spanning the cell membrane. Each integrin has three distinct structural domains.
The extracellular domain extends outside the cell, responsible for binding to specific molecules in the extracellular matrix, such as fibronectin, collagen, or laminin, or to proteins on other cell surfaces. This extracellular part forms an elongated stalk with a globular head region where ligand binding occurs. The alpha subunit’s head region often contains seven repeating segments that fold into a beta-propeller structure, while the beta subunit has an “I-like” domain that also participates in ligand binding.
A single-pass transmembrane domain connects the extracellular domain to the cell’s interior, anchoring the integrin within the cell’s outer membrane. This segment ensures the integrin is securely embedded, allowing it to transmit signals across the membrane. A short cytoplasmic tail extends into the cell’s cytoplasm, typically less than 75 amino acids for most beta subunits. The beta-4 subunit is a notable exception with a much longer tail. This cytoplasmic tail interacts with the cell’s internal machinery, including the cytoskeleton and various signaling proteins, linking the external environment to intracellular events.
Conformational Changes and Activation
Integrins are dynamic molecules that undergo significant conformational changes to become active and functional. In their inactive state, integrins adopt a bent, low-affinity conformation where the extracellular head region is folded close to the membrane. This “closed” state limits their ability to bind effectively to ligands.
Upon activation, integrins transition to an extended, high-affinity conformation, where the extracellular domains unbend and separate. This exposes the ligand-binding sites, allowing for stronger and more stable interactions with their targets. This process can be initiated by signals from within the cell, known as “inside-out signaling”. Intracellular proteins, such as talin, bind to the integrin’s cytoplasmic tails, causing separation of the alpha and beta cytoplasmic domains and leading to the extension and activation of the extracellular portion.
Integrins can also be activated by signals from outside the cell through “outside-in signaling”. This occurs when extracellular ligands bind to the integrin’s extracellular domain, which in turn triggers conformational changes that transmit signals into the cell’s interior. These structural shifts are reciprocal; ligand binding affects integrin conformation, and integrin conformation affects ligand binding, creating a feedback loop. The precise mechanisms involving these structural shifts, including the hinging of the “legs” and the movement of specific domains, are crucial for regulating integrin function and their ability to transmit mechanical and biochemical cues across the cell membrane.
Structural Basis of Cellular Functions
The structure of integrins and their dynamic conformational changes underpin their diverse roles in cellular processes. The extracellular domain’s capacity to bind various ligands, such as fibronectin, collagen, laminin, or other cell surface proteins, enables cells to adhere to their surroundings and to each other. This binding is often facilitated by divalent cations, such as magnesium or manganese, necessary for the integrin to attain its extended, active structure. This adhesion is fundamental for maintaining tissue integrity and allowing cells to sense their physical environment.
Beyond simple adhesion, integrin interaction with ligands also facilitates cell migration. As cells move, integrins dynamically form and break connections with the extracellular matrix, allowing the cell to pull itself forward. The cytoplasmic tail, while short for most, plays a profound role by interacting with components of the cell’s cytoskeleton, particularly actin filaments, and with numerous signaling molecules. This physical linkage between the outside and inside of the cell allows integrins to act as signal transducers, relaying information about the extracellular environment into the cell.
This bidirectional signaling allows integrins to not only receive external cues and transmit them inward (outside-in signaling), but also respond to internal cellular signals by changing their ligand-binding affinity (inside-out signaling). These signaling events influence a wide array of intracellular processes, including cell growth, proliferation, differentiation, survival, and the organization of the intracellular cytoskeleton. For instance, the binding of ligands can recruit intracellular signaling molecules to the integrin’s cytoplasmic domains, activating pathways that mediate cellular functions.
Variety Among Integrins
The family of integrins exhibits diversity, which arises from the numerous combinations of alpha and beta subunits that can form a functional heterodimer. In humans, there are 18 known alpha subunits and 8 known beta subunits. These subunits can combine in various ways, leading to the formation of at least 24 distinct integrin heterodimers, each with unique characteristics.
This structural variety results in a wide range of ligand specificities among different integrins. For example, some integrins bind to ligands containing an RGD (arginine-glycine-aspartic acid) tripeptide motif, while others recognize different amino acid sequences or specific protein structures. This means that different integrin combinations are tailored to bind to particular components of the extracellular matrix or to specific counter-receptors on other cells.
The diverse combinations of alpha and beta subunits also contribute to their varied roles in different tissues and cellular contexts. For instance, certain integrins are expressed in leukocytes and are involved in immune responses, while others are found in platelets and play a role in blood clotting. This specialization ensures that cells can interact with their specific microenvironment in a highly regulated and context-dependent manner, allowing for the fine-tuning of cell adhesion, migration, and signaling in various physiological processes.