The inter-α-inhibitor family: from structure to regulation

Abstract

Inter-alpha-inhibitor (IalphaI) and related molecules, collectively referred to as the IalphaI family, are a group of plasma protease inhibitors. They display attractive features such as precursor polypeptides that give rise to mature chains with quite distinct fates and functions, and inter-chain glycosaminoglycan bonds within the various molecules. The discovery of an ever growing number of such molecules has raised pertinent questions about their pathophysiological functions. The knowledge of this family has long been structure-oriented, whereas the structure/function and structure/regulation relationships of the family members and their genes have been largely ignored. These relationships are now being elucidated in events such as gene transcription, precursor processing, changes in plasma protein levels in health and disease and binding capacities that involve hyaluronan as well as other plasma proteins as ligands. This review presents some recent progress made in these fields that paves the way for an understanding of the functions of IalphaI family members in vivo. Finally, given the wealth of heterogeneous, complicated and sometimes contradictory nomenclatures and acronyms currently in use for this family, a new, uniform, nomenclature is proposed for IalphaI family genes, precursor polypeptides and assembled proteins.

Structural Characterization of Inter-α-inhibitor

“…It consists of bikunin, which has a molecular mass of about 25 kDa (1,2), and two other polypeptides of 75-80 kDa, the heavy chains 1 and 2 (H1 and H2) (3). Bikunin carries a 7-kDa chondroitin sulfate chain (4,5), which is linked to the ␣-carbons of the C-terminal amino acid residues of H1 and H2 through two ester bonds (6).…”

Inhibition of tumor growth and metastatic spreading by overexpression of inter‐alpha‐trypsin inhibitor family chains

“…The most of ITI members are composed of variable associations of light (ITI-L) and heavy chains (ITI-H1, -H2, -H3), encoded by 4 different genes on 3 chromosomes, 6 -9 giving rise to a series of proteins covalently linked by a glycosaminoglycan 10 and differing in their chain composition. 11 Although the binding of ITI to HA is known for a long time, 12 involvement of heavy chains in this linkage was only recently demonstrated [13][14][15] together with a major role in the ECM stability of the mouse cumulus oocyte complex. 16 The ITI-L chain mRNA encodes 2 tandemly arranged proteins that separate after proteolytic cleavage: the ␣ 1 -microglobulin (␣ 1 m) that belongs to the lipocalin superfamily 17 and the bikunin that contains 2 Kunitz inhibitory domains responsible for the protease inhibitory activity of ITI molecules.…”

Human Serum Proteins Recognized by CA215 and Cancerous Immunoglobulins and Implications in Cancer Immunology

“…Inter-α-trypsin inhibitor heavy chain 4 is a fragment of the inter-α-trypsin inhibitor heavy chain 4, which is a type II acute phase protein secreted by the liver (Pineiro et al, 1999;Salier, Rouet, Raguenez, & Daveau, 1996). It has plasma kallikrien sensitivity, and is O glycosylated and assumed to not undergo further cleavage or modification (Nishimura et al, 1995).…”