Identification and cloning of two isoforms of human high-temperature requirement factor A3 (HtrA3), characterization of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2.
In the present study, we identified an additional member of the human high-temperature requirement factor A (HtrA) protein family, called pregnancy-related serine protease or HtrA3, which was most highly expressed in the heart and placenta. We cloned the full-length sequences of two forms (long and short) of human HtrA3 mRNA, located the gene on chromosome 4p16.1, determined its genomic structure and revealed how the two mRNA variants are produced through alternative splicing. The alternative splicing was also verified by Northern blotting. Four distinct domains were found for the long form HtrA3 protein: (i) an insulin/insulin-like growth factor binding domain, (ii) a Kazal-type S protease-inhibitor domain, (iii) a trypsin protease domain and (iv) a PDZ domain. The short form is identical to the long form except it lacks the PDZ domain. Comparison of all members of human HtrA proteins, including their isoforms, suggests that both isoforms of HtrA3 represent active serine proteases, that they may have different substrate specificities and that HtrA3 may have similar functions to HtrA1. All three HtrA family members showed very different mRNA-expression patterns in 76 human tissues, indicating a specific function for each. Interestingly, both HtrA1 and HtrA3 are highly expressed in the placenta. Identification of the tissue-specific function of each HtrA family member is clearly of importance.
Nie
Gui-Ying
GY
Prince Henry's Institute of Medical Research, P.O. Box 5152, 246 Clayton Road, Clayton, Victoria 3168, Australia. guiying.nie@med.monash.edu.au
Hampton
Anne
A
Li
Ying
Y
Findlay
Jock K
JK
Salamonsen
Lois A
LA
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002894:Chromosomes, Human, Pair 4; D003001:Cloning, Molecular; D005260:Female; D005786:Gene Expression Regulation; D000074289:High-Temperature Requirement A Serine Peptidase 1; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010920:Placenta / Q000502:physiology; D011247:Pregnancy; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D040681:Structural Homology, Protein
D024101:Mitochondrial Proteins; D020033:Protein Isoforms; C474013:HTRA3 protein, human; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse