Crystal structure of the mature extracellular domain of IA 2 unveils similarity to mucins.

PRIMO ME,; KLINKE S,; GOLDBAUM FA,; POSKUS E; ERMÁCORA MR

Acapulco (México)

Congreso; 2nd Latin American protein society meeting; 2007

The 106‑kDa insulinoma–associated protein (IA–2), a member of the receptor protein tyrosine phosphatase superfamily, is located in the membrane of secretory granules (SGs) of neural, pituitary and pancreatic islet cells. It became known because it is related to insulin secretion and autoimmunity disorders in diabetes. IA‑2 is post‑translationally processed by proteolytic cleavage, yielding a mature extracellular domain (meIA‑2, residues 449-576), attached to the naturally inactive intracellular domain (IA-2ic) through a single transmembrane region (residues 576‑600). In a previous work we reported that meIA‑2 is an autonomous folding unit and now we determined its 3D structure by X‑ray diffraction with 1.3‑Å resolution. Unexpectedly, the solved structure only includes residues 469-557, which was confirmed by mass analysis. Further investigation demonstrated that auto proteolysis of the chain extremes takes place during crystallization. The fragment of meIA‑2 has a b1‑a1‑b2‑b3‑a2‑b4 fold, in which the helices rest on top of a beta sheet. This fold correspond to the SEA domain typical of glycosylated extracellular domains, like those found in mucins. MeIA‑2 was found to dimerize in solution, and in the crystal, meIA‑2 exhibits two different dimerization modes that might be relevant in vivo and permit the its interaction with a plethora of extracellular moieties and membranes.