KLK6 (kallikrein-related peptidase 6)

	Graphic illustration of the KLK6 gene. Boxes denote exons and connecting lines represent introns. The coding sequences are colored in green, while 5' and 3' untranslated regions (UTRs) are shown in white. The numbers inside or outside boxes indicate lengths (nt) of exons and introns, respectively, while the numbers in parentheses indicate lengths (aa) of protein isoforms. Arrows mark the position of the start codons (ATG) and asterisks (*) mark the position of the stop codon (TGA). The figure is drawn in scale, except for the introns containing the (//) symbol. For each transcript, the splice variant number, the GenBank accession number and the protein isoform number are shown next to each transcript (Adamopoulos et al., 2017).
Description	The KLK6 gene is located on 19q chromosome, has a total length of 11.043 nt, and consists of 7 exons and 6 introns.
Transcription	KLK6 pre-mRNA is subjected to alternative splicing. Six (6) variants had previously been detected, while another 6 transcripts have recently been identified by our research group (Adamopoulos et al., 2017). Furthermore, one more variant is predicted, based on similarity to 50 ESTs. Each of them has a different exon and intron structure. The main variant (variant A) consists of 7 exons and 6 introns. The first 2 introns do not include coding regions and compose the 5UTR. The other 11 variants range from 3 to 7 exons and 2 to 6 introns, while some of them bare similarity to each other. The structures of all variants are clearly illustrated in Figure 1.
Pseudogene	Not detected so far.

	Alignment of 4 out of the 8 isoforms of the KLK6 protein. The signal peptide, glycosylation site, catalytic triad, and disulfide bonds are marked on the main isoform (isoform 1). The other four isoforms that are not presented align only partially with the main isoform.
Description	Eight different isoforms of KLK6 protein have been detected, consisting of 244, 137, 120, 149, 42, 138 277, and 182 amino acid (aa) residues, respectively. The KLK6 gene encodes a single-chain pre-proenzyme, which is enzymatically inactive. After the removal of the signal peptide (16 aa) from the pre-proenzyme, an inactive proKLK is formed and secreted to the extracellular space, where it is finally transformed into the active KLK through further cleavage (Bayani & Diamandis, 2011).
Expression	KLK6 is highly expressed in cerebral cortex, tonsil, spleen, esophagus, kidney, fallopian tube and breast.
Localisation	KLK6 is mainly localized to nucleoplasm, nuclear membrane and cytokinetic bridge.
Function	KLK6 is a serine protease, involved in proteolytic cascades. KLK6 has been suggested to be autoactivated or activate other proKLKs. When activated, serine proteases are usually regulated by binding to serpins (serine protease inhibitors), which prompts to their inactivation. A preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position is detected in KLK6 substrate. Three amino acid residues (positions: 62, 106, and 197) constitute the catalytic triad in the main protein isoform (isoform 1, 244 aa) that is responsible for serine protease activity. An Asp residue at position 191 suggests a trypsin-like activity, while chymotrypsin activity is suggested by a loop similar to chymotrypsin 3D-structure. However, chymotrypsin activity is rejected by recent studies. KLK6 is activated against amyloid precursor protein, which is associated with Alzheimer's disease, myelin basic protein, and casein. Furthermore, it participates in the degradation of extracellular matrix (ECM) proteins, namely fibronectin, laminin, vitronectin, laminin and collagen. It is involved in alpha-synuclein degradation and in the inhibition of its polymerization. This fact demonstrates the potential role of KLK6 in Parkinson's disease. Furthermore, KLK6 plays a role in cancer invasion and metastasis (Bayani & Diamandis, 2011).

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