Abstract
Recognition of laminin by integrin receptors is central to the epithelial cell adhesion to basement membrane, but the structural background of this molecular interaction remained elusive. Here, we report the structures of the prototypic laminin receptor α6β1 integrin alone and in complex with three-chain laminin-511 fragment determined via crystallography and cryo-electron microscopy, respectively. The laminin-integrin interface is made up of several binding sites located on all five subunits, with the laminin γ1 chain C-terminal portion providing focal interaction using two carboxylate anchor points to bridge metal-ion dependent adhesion site of integrin β1 subunit and Asn189 of integrin α6 subunit. Laminin α5 chain also contributes to the affinity and specificity by making electrostatic interactions with large surface on the β-propeller domain of α6, part of which comprises an alternatively spliced X1 region. The propeller sheet corresponding to this region shows unusually high mobility, suggesting its unique role in ligand capture.
Highlights
Recognition of laminin by integrin receptors is central to the epithelial cell adhesion to basement membrane, but the structural background of this molecular interaction remained elusive
LM511 by cryoelectron microscopy (cryo-electron microscopy (EM)), which is rapidly growing as a critical method for integrin structural determination[47,48]
In many published structures of RGD-binding integrins in complex with RGD-like ligands, the “D” in the ligand invariably serves as the primary anchor point to engage Metal-Ion-Dependent Adhesion Site (MIDAS)-bound cation, while the “R” or equivalent basic residue at the -2 position is often bound by specific residue(s) in the α subunit (e.g., α5-Q221/D227, αVD218, and αIIb-D224, denoted by red in Fig. 5e), there are few exceptions to this rule[50]
Summary
Recognition of laminin by integrin receptors is central to the epithelial cell adhesion to basement membrane, but the structural background of this molecular interaction remained elusive. We12 and others[13] have succeeded in recombinantly producing E8 fragment of human LM511 and mouse LM111 (mLM111) and solved their crystal structures at 1.80 and 2.13 Å resolutions, respectively. These structures revealed the architecture of the E8 fragment, where the coiled-coil domain that bundles the α/β/γ chains and the closely-arranged three laminin globular (LG) domains (LG1-3) of the α chain form a ladle-like shape. We have provided evidence that the C-terminal region of the LMγ1 chain (referred to as LMγ1-tail or γ1-tail hereafter) and the bottom face of the LG domains conspire to form integrin binding interface, we have been unable to show that LMγ1-tail peptides can directly bind to integrins as many RGD-based peptides and mimetic compounds do, making it difficult to reach a consensus about the identity of the binding site(s)
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