Molecular Biology: Protein Structure and Functions - Stepanov V.M. 2005

Fibrous proteins
Laminin

Laminin is a protein involved in The formation of the Extracellular matrix and Cell anchoring. Composed of very long polypeptide chains, its geometry might suggest it belongs to Fibrous Proteins; however, quite extensive Regions of the molecule consist of small globular chains structurally similar to certain growth factors. Thus, laminin cannot be strictly classified as a traditional fibrous protein, although its molecular contours and functional properties share much in common with them.

This glycoprotein, with a Molecular Weight of approximately 900 kDa, is a major component of the basement membrane upon which Connective Tissue forms. Several laminins are known, differing in structural details and tissue localization, indicating that they constitute a whole family of structural, multi-domain proteins.

Laminin binds to type IV Collagen, characteristic of the basement membrane, as well as heparan sulfate, Proteoglycans, and other macromolecules, notably nidogen—the major basement membrane protein—resulting in the formation of a multi-component network Structure known as the matrix. In addition, laminin mediates the attachment of epithelial Cells to the basement membrane. Laminin (Fig. 14.5) is built from three polypeptide chains: the A-chain (molecular weight 440 kDa), the B1-chain (225 kDa), and the B2-chain (205 kDa). The C-terminal regions of all three chains can form highly extended a-helices composed of numerous heptad repeats characteristic of coiled-coil proteins, such as Keratins.

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Fig. 14.5. Structural Organization of laminin.

A, B1, and B2 are The polypeptide chains, with their C-termini located at the bottom of the figure. The parallel-directed helical regions apparently form a single coiled-coil. One of its segments is responsible for neurite outgrowth and nerve Cell Adhesion. G is a large globule formed by the C-terminal region of the A-chain.

Roman numerals denote domains within the polypeptide chains of laminin. Domain III of the B chain is responsible for binding to The Cell surface receptor and contains the Tyr—Ile—Ser—Gly—Arg sequence. The N-terminal globular domains of the B1 and B2 chains bind type IV collagen.

Apparently, the C-terminal a-helical regions of all three chains are wound into a single, highly rigid, rod-like structure—a coiled-coil about 700–800 Å long—which terminates in a globule formed by the protruding C-terminal segment of the A-chain. The N-terminal portion of the A-chain likely forms several domains, including the so-called Cysteine-rich regions, where there are approximately 8 cysteine residues per 50 Amino Acids. These domains are structurally analogous to epidermal growth factor (EGF), possess a rigid rod-like structure, and, notably, are frequently found in animal proteins.

The N-terminal segments of the B1 and B2 chains are, so to speak, folded away from the corresponding segment of the A chain, giving the laminin molecule a cross-like shape formed by three short arms and one long arm, with each of the three short rays terminating in two small globules and the long one in a single large globule. The central part of the cruciform structure is stabilized by several Disulfide Bonds. The N-terminal portions of the light B1 and B2 chains also form two globular domains each, along with rigid rod-like structures constructed similarly to epidermal growth factor (EGF).

One of such EGF domains in the B1 chain contains the recognition site for the laminin receptor located on the cell surface. This region is responsible for cell adhesion and directed migration. Characteristically, a relatively short pentapeptide—a sequence fragment within this laminin domain with the structure Tyr—Ile—Gly—Ser—Arg—can compete with laminin for interaction with the cell receptor and inhibit cell adhesion, including, for example, melanoma cells interacting with the basement membrane. The binding of type IV collagen, a characteristic component of the basement membrane, is mediated by globules on the short arms of the cross, while the nidogen-binding site (150 kDa) is located in the EGF-like domain of the B2 chain.