Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases.
Two dipeptidyl peptidase IV (DPPIV, DPP4)-related proteins, DPP8 and DPP9, have been identified recently [Abbott, Yu, Woollatt, Sutherland, McCaughan, and Gorrell (2000) Eur. J. Biochem. 267, 6140-6150; Olsen and Wagtmann (2002) Gene 299, 185-193; Qi, Akinsanya, Riviere, and Junien (2002) Patent application WO0231134]. In the present study, we describe the cloning of DPP10, a novel 796-amino-acid protein, with significant sequence identity to DPP4 (32%) and DPP6 (51%) respectively. We propose that DPP10 is a new member of the S9B serine proteases subfamily. The DPP10 gene is located on the long arm of chromosome 2 (2q12.3-2q14.2), close to the DPP4 (2q24.3) and FAP (2q23) genes. The active-site serine residue is replaced by a glycine residue in DPP10, resulting in the loss of DPP activity. The serine residue is also replaced in DPP6, which lacks peptidase activity. DPP8 and DPP9 share an identical active site with DPP4 (Gly-Trp-Ser-Tyr-Gly). In contrast with the previous results suggesting that DPP9 is inactive, we show that DPP9 is a DPP, hydrolysing Ala-Pro-(7-amino-4-methyl-coumarin) with similar pH-specificity and protease-inhibitor-sensitivity to those of DPP4 and DPP8. Northern-blot analysis shows that whereas DPP8 and DPP9 are widely expressed, DPP10 is expressed mainly in the brain and pancreas. DPP6, which has the highest amino acid identity with DPP10, has been shown previously [Nadal, Ozaita, Amarillo, de Miera, Ma, Mo, Goldberg, Misumi, Ikehara, Neubert et al. (2003) Neuron 37, 449-461] to associate with A-type K(+) channel subunits, modulating their transport and function in somatodendritic compartments of neurons. It is possible that DPP10 is involved in similar functions in the brain. Elucidation of the physiological or pathophysiological role of DPP8, DPP9 and DPP10 and characterization of their structure-function relationships will add impetus to the development of inhibitor molecules for pharmacological or therapeutic use.
Qi
Shu Y
SY
Molecular and Cellular Biology Department, Ferring Research Institute, 3550 General Atomics Court, San Diego, CA 92121-1122, USA.
Riviere
Pierre J
PJ
Trojnar
Jerzy
J
Junien
Jean-Louis
JL
Akinsanya
Karen O
KO
D000595:Amino Acid Sequence; D001483:Base Sequence; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003001:Cloning, Molecular; D017931:DNA Primers; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D020224:Expressed Sequence Tags; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4; D012697:Serine Endopeptidases