Abstract
Dystroglycan (DG) is an adhesion complex that links the cytoskeleton to the surrounding extracellular matrix in skeletal muscle and a wide variety of other tissues. It is composed of a highly glycosylated extracellular α-DG associated noncovalently with a transmembrane β-DG whose cytodomain interacts with dystrophin and its isoforms. Alpha-dystroglycan (α-DG) binds tightly and in a calcium-dependent fashion to multiple extracellular proteins and proteoglycans, each of which harbors at least one, or, more frequently, tandem arrays of laminin-globular (LG) domains. Considerable biochemical and structural work has accumulated on the α-DG-binding LG domains, highlighting a significant heterogeneity in ligand-binding properties of domains from different proteins as well as between single and multiple LG domains within the same protein. Here we review biochemical, structural, and functional information on the LG domains reported to bind α-dystroglycan. In addition, we have incorporated bioinformatics and modeling to explore whether specific motifs responsible for α-dystroglycan recognition can be identified within isolated LG domains. In particular, we analyzed the LG domains of slits and agrin as well as those of paradigmatic α-DG non-binders such as laminin-α3. While some stretches of basic residues may be important, no universally conserved motifs could be identified. However, the data confirm that the coordinated calcium atom within the LG domain is needed to establish an interaction with the sugars of α-DG, although it appears that this alone is insufficient to mediate significant α-DG binding. We develop a scenario involving different binding modes of a single LG domain unit, or tandemly repeated units, with α-DG. A variability of binding modes might be important to generate a range of affinities to allow physiological regulation of this interaction, reflecting its crucial biological importance.
Highlights
In the tissues of multicellular animals, different cell types establish intercellular molecular contacts as well as cellular-extracellular ones
Like legume lectins as well as animal galectins, with which they share a similar fold (Rudenko et al, 2001), the LG domains establish crucial protein-sugar interactions to stabilize sarcolemma and other plasma membranes. It has recently been shown (Briggs et al, 2016) that the recombinant LG4-5: 2JD4 (LG4)-LG5 pair of murine laminin-α2 can be crystallized in combination with a polysaccharide that is found in α-DG and belongs to its glycan-repeated scaffold (Willer et al, 2014); this important study demonstrates the crucial role of a coordinated calcium cation for binding
We speculate that this basic “patch” may serve as an additional site for the α-Dystroglycan/Binding to LG Domains
Summary
In the tissues of multicellular animals, different cell types establish intercellular molecular contacts (junctions) as well as cellular-extracellular ones. Like legume lectins as well as animal galectins, with which they share a similar fold (Rudenko et al, 2001), the LG domains establish crucial protein-sugar interactions to stabilize sarcolemma and other plasma membranes In this regard, it has recently been shown (Briggs et al, 2016) that the recombinant LG4-LG5 pair of murine laminin-α2 can be crystallized in combination with a polysaccharide that is found in α-DG and belongs to its glycan-repeated scaffold (Willer et al, 2014); this important study demonstrates the crucial role of a coordinated calcium cation for binding. In the past 20 years considerable biochemical and structural data (see Table 1) have been collected on laminins (the prototypical LG-containing DG binding partners) and on several other DG binding partners, several key questions concerning dystroglycan-LG binding remain unanswered Is it possible to identify common molecular characteristics (ideally short linear motifs) that would define the propensity to bind α-DG in this domain family? The specific β-strand order, as found in perlecan LG3, JIHCLAN and GFEDKBM (in the two opposing β-sheets, respectively, see Figure 2) applies broadly to all the LG domains α-Dystroglycan/Binding to LG Domains
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