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176 a.a.
_CA
Key reference
DOI no: 10.1016/j.str.2004.02.001 Structure 12:503-515 (2004) PubMed id: 15016366
Modulation of agrin function by alternative splicing and Ca2+ binding. J.Stetefeld, A.T.Alexandrescu, M.W.Maciejewski, M.Jenny, K.Rathgeb-Szabo, T.Schulthess, R.Landwehr, S.Frank, M.A.Ruegg, R.A.Kammerer. ABSTRACT
The aggregation of acetylcholine receptors on postsynaptic membranes is a key step in neuromuscular junction development. This process depends on alternatively spliced forms of the proteoglycan agrin with "B-inserts" of 8, 11, or 19 residues in the protein's globular C-terminal domain, G3. Structures of the neural B8 and B11 forms of agrin-G3 were determined by X-ray crystallography. The structure of G3-B0, which lacks inserts, was determined by NMR. The agrin-G3 domain adopts a beta jellyroll fold. The B insert site is flanked by four loops on one edge of the beta sandwich. The loops form a surface that corresponds to a versatile interaction interface in the family of structurally related LNS proteins. NMR and X-ray data indicate that this interaction interface is flexible in agrin-G3 and that flexibility is reduced by Ca(2+) binding. The plasticity of the interaction interface could enable different splice forms of agrin to select between multiple binding partners.
Selected figure(s)
Figure 7.
Figure 7. Comparison of Charge Distribution in Calcium Bound G Domains(A) The G5 domain of the a2 chain of laminin (Hohenester et al., 1999). Basic residues important in binding of a-DG to laminin are labeled green.(B) Calcium-bound NMR structure of the agrin-G3 B0 domain.(C) Calcium-bound B8 X-ray structure.(D) Calcium-bound B11 X-ray structure. The calcium binding site is indicated in the laminin structure, but is left out for clarity in the agrin structures (conserved red cavity). The GRASP diagrams were made using the "full.crg" charge/radius file and are colored according to an electrostatic potential ramp ranging from +5 e kT -1 (blue, positive) to -5 e kT -1 (red, negative). The calcium ion was not included in electrostatic calculations. The position of the calcium binding site (conserved red cavity) is indicated in the laminin structure.The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 503-515) copyright 2004. Figure was selected by the author.
Author's comment Briefly the function of this particular domain is:
Function 1. To stimulate the clustering of acetylcholine receptors on the postsynaptic (muscle) side of nerve-muscle synapses. It does this indirectly by activating MuSK, a muscle specific tyrosine kinase. This activity is only present in alternative mRNA-spliced forms of agrin that originate in neural cells. These isoforms have sequence inserts of 8, 11, or 19 residues in the loop between the second and third strands of beta-sheet in the G3 domain.
Function 2. To bind in conjunction with the other G domains in agrin (G1 and G2) to the glycan chains of alpha-dystroglycan emanating from muscle. This is presumably the role of the insert-less B0 isoform that lack the acetylcholine receptor clustering activity associated with the neural isoforms. Binding to alpha-dystroglycan is thought to play a structural role, maintaining the integrity of the connection between the neuromuscular junction basal lamina and muscle.
Both of these functions require calcium, and the G3 domain has a calcium binding site near the sequence insert site. There are other functions in the CNS and the protein is found in an insoluble form bound to Alzheimer's plaques but those aspects are currently not as well understood.
Andrei Alexandrescu
Literature references that cite this PDB file's key reference
PubMed id Reference
19553699 F.Carafoli, N.J.Clout, and E.Hohenester (2009).
Crystal structure of the LG1-3 region of the laminin alpha2 chain.J Biol Chem, 284, 22786-22792.
PDB code: 2wjs
17553797 V.M.Leppänen, H.Tossavainen, P.Permi, L.Lehtiö, G.Rönnholm, A.Goldman, I.Kilpelaïnen, and T.Pihlajamaa (2007).
Crystal structure of the N-terminal NC4 domain of collagen IX, a zinc binding member of the laminin-neurexin-sex hormone binding globulin (LNS) domain family.J Biol Chem, 282, 23219-23230.
PDB code: 2uur
16772286 L.R.Sheckler, L.Henry, S.Sugita, T.C.Südhof, and G.Rudenko (2006).
Crystal structure of the second LNS/LG domain from neurexin 1alpha: Ca2+ binding and the effects of alternative splicing.J Biol Chem, 281, 22896-22905.
PDB code: 2h0b
17012237 P.Scotton, D.Bleckmann, M.Stebler, F.Sciandra, A.Brancaccio, T.Meier, J.Stetefeld, and M.A.Ruegg (2006).
Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin.J Biol Chem, 281, 36835-36845.
15576561 A.T.Alexandrescu (2005).
Amyloid accomplices and enforcers.Protein Sci, 14, 1. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
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