Spinesin/TMPRSS5, a Novel Transmembrane Serine Protease, Cloned from Human Spinal Cord

Abstract

A cDNA encoding a novel serine protease, which we designated spinesin, has been cloned from human spinal cord. The longest open reading frame was 457 amino acids. A homology search revealed that the human spinesin gene was located at chromosome 11q23 and contained 13 exons, the gene structure being similar to that of TMPRSS3 whose gene is also located on 11q23. Spinesin has a simple type II transmembrane structure, consisting of, from the N terminus, a short cytoplasmic domain, a transmembrane domain, a stem region containing a scavenger receptor-like domain, and a serine protease domain. Unlike TMPRSS3, it carries no low density lipoprotein receptor domain in the stem region. The extracellular region carries five N-glycosylation sites. The sequence of the protease domain carried the essential triad His, Asp, and Ser and showed some similarity to that of TMPRSS2, hepsin, HAT, MT-SP1, TM-PRSS3, and corin, sharing 45.5, 41.9, 41.3, 40.3, 39.1, and 38.5% identity, respectively. The putative mature protease domain preceded by H 6 DDDDK was produced in Escherichia coli, purified, and successfully activated by immobilized enterokinase. Its optimal pH was about 10. It cleaved synthetic substrates for trypsin, which is inhibited by p-amidinophenylmethanesulfonyl fluoride hydrochloride but not by antipain or leupeptin. Northern blot analysis against mRNA from human tissues including liver, lung, placenta, and heart demonstrated a specific expression of spinesin mRNA in the brain. Immunohistochemically, spinesin was predominantly expressed in neurons, in their axons, and at the synapses of motoneurons in the spinal cord. In addition, some oligodendrocytes were clearly stained. These results indicate that spinesin is transported to the synapses through the axons after its synthesis in the cytoplasm and may play important roles at the synapses. Further analyses are required to clarify its roles at the synapses and in oligodendrocytes.

Matriptase-2, a Membrane-bound Mosaic Serine Proteinase Predominantly Expressed in Human Liver and Showing Degrading Activity against Extracellular Matrix Proteins

“…Recently, a HAT-related protease isolated from rat tissues has been found to cleave pro-␥-melanotropin at the adrenal cortex, stimulating the mitogenic actions of this peptide (19). Spinesin, predominantly expressed at synapses, may play specific roles in neural functions (20). Finally, insertion of ␤-satellite repeats into the gene encoding TMPRSS3 causes a form of autosomal recessive deafness, suggesting a role for this protease in the development or maintenance of the inner ear or in the turnover of the protein contents of the perilymph and endolymph (21).…”

The Structure of Human Prokallikrein 6 Reveals a Novel Activation Mechanism for the Kallikrein Family

“…This causes significant structural changes in this loop and in that of the disulfide-connected segment Gly 216 -Gly 226 , endowing hK6 with a slightly different substrate specificity upon maturation. Both proteins have been detected in mammalian brain (32) and, like other homologues such as myelencephalonspecific protease (71), KLK14 (72), reelin (73), spinesin (74), and neurotrypsin (75), show higher expression levels in the central nervous system than in most peripheral tissues. A recent report has even shown that high levels of plasma kallikrein are present in the brain, where it could play a role in the nervous system (76).…”

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

“…41 Interestingly, overexpression of DESC1 has been documented in tumors derived from kidney, brain and breast tissues, suggesting a pro-tumorigenic function depending on the tissue of origin. 47 The second largest of the sub-families, hepsin/ TMPRSS/enteropeptidase contains TMPRSS 2-5, [48][49][50] MSPL, 51 hepsin and enteropeptidase. The most comprehensively described member of this sub-family, enteropeptidase, functions near the apex of a proteolytic cascade of digestive enzymes through its conversion of trypsinogen to trypsin.…”