A Novel Family of Cathepsin L-like (CTSLL) Sequences on Human Chromosome 10q and Related Transcripts

Bryce, Steven D.; Sj, Lindsay; Gladstone, A.J.; Braithwaite, K. S.; Chapman, C.G.; Spurr, N.K.; Lunec, John

doi:10.1006/geno.1994.1667

Cited by 14 publications

(11 citation statements)

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“…Expression of the proximal paralogs is less surprising, given their interstitial positions and the fact that several of the Cathepsin L pseudogenes on 10q (CSTLL2 and CSTLL3) are also expressed (Bryce et al 1994). Despite this, we can find no clear evidence to indicate that any of these transcripts are expressed at a high level or have the potential to encode novel proteins.…”

Section: Kiaa0187: a Structurally Heterogeneous Expressed Pseudogene mentioning

confidence: 80%

“…Numbers refer to the clones shown in F. The GLUD1-related sequences identified include the functional GLUD1 gene (within hit 8) and two nonprocessed pseudogene fragments, one of which (GLUDP3 within hit 4) has been previously mapped to 10q22 (Deloukas et al 1993). The Cathepsin L-related sequences include two pseudogenes, CTSLL1 and CTSLL1-2 (within hits 10 and 1, respectively), which have been mapped previously to 10q (Bryce et al 1994). (B-D) Dot matrix analyses of 10q pseudogene clusters.…”

Section: Distal and Proximal Paralogs: Subfamilies Created By Two Dismentioning

confidence: 99%

“…The functional GLUD1 gene was assigned to 10q23 in 1989 (Jung et al 1989), and although at least five human paralogs exist, the only nonprocessed paralogs identified to date map to 10q (Deloukas et al 1993; present study). The active Cathepsin L gene maps to 9q21-22 (Fan et al 1989), but again, all pseudogenes identified to date map to 10q (Bryce et al 1994; present study), and sequence analysis indicates that these have been created following a single duplication of the active gene from chromosome 9 to 10 ∼40 to 50 Myr ago (Bryce et al 1994). Furthermore, although the functional KIAA1099 gene maps to 2q24 (Unigene cluster Hs159377), all chromosome 10 paralogs of this gene are processed, indicating that the chromosome 10 paralogs have been formed subsequent to an RNA-mediated transposition event from chromosome 2 to 10.…”

Section: Distal and Proximal Paralogs: Subfamilies Created By Two Dismentioning

confidence: 99%

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Human Paralogs of KIAA0187 Were Created through Independent Pericentromeric-Directed and Chromosome-Specific Duplication Mechanisms

Crosier¹

2002

Genome Res.

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KIAA0187 is a gene of unknown function that maps to 10q11 and has been subject to recent duplication events. Here we analyze 18 human paralogs of this gene and show that paralogs of exons 14-23 were formed through satellite-associated pericentromeric-directed duplication, whereas paralogs of exons 1-9 were created via chromosome-specific satellite-independent duplications. In silico, Northern, and RT-PCR analyses indicate that nine paralogs are transcribed, including four in which KIAA0187 exons are spliced onto novel sequences. Despite this, no new genes appear to have been created by these events. The chromosome 10 paralogs map to 10q11, 10q22, 10q23.1, and 10q23.3, forming part of a complex family of chromosome-specific repeats that includes GLUD1, Cathepsin L, and KIAA1099 pseudogenes. Phylogenetic analyses and comparative FISH indicates that the 10q23.1 and 10q23.3 repeats were created in 10q11 and relocated by a paracentric inversion 13 to 27 Myr ago. Furthermore, the most recent duplications, involving the KIAA1099 pseudogenes, have largely been confined to 10q11. These results indicate a simple model for the evolution of this repeat family, involving multiple rounds of centromere-proximal duplication and dispersal through intrachromosomal rearrangement. However, more complex events must be invoked to account for high sequence identity between some paralogs.

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Section: Kiaa0187: a Structurally Heterogeneous Expressed Pseudogene mentioning

confidence: 80%

Section: Distal and Proximal Paralogs: Subfamilies Created By Two Dismentioning

confidence: 99%

Section: Distal and Proximal Paralogs: Subfamilies Created By Two Dismentioning

confidence: 99%

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Human Paralogs of KIAA0187 Were Created through Independent Pericentromeric-Directed and Chromosome-Specific Duplication Mechanisms

Crosier¹

2002

Genome Res.

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“…CTLA-2␣ and ␤, on the other hand, are 13 residues longer than the proregion of cathepsin L, so that they could have arisen by a duplication of the first five exons of the procathepsin L. Another plausible explanation is a point mutation in a copy of a procathepsin L gene giving rise to a premature stop codon. Several pseudogenes of procathepsin L have been found in human (47), estimated to have arisen by a duplication event 40 -50 million years ago. Three of them were sequenced, and stop codons were found at amino acid positions 35 and 59 of the proregion.…”

Section: Discussionmentioning

confidence: 99%

pH-induced Conformational Transitions of the Propeptide of Human Cathepsin L

Jerala

Žerovnik

Kidrič

et al. 1998

Journal of Biological Chemistry

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Synthesis of proteases as inactive zymogens is a very important mechanism for the regulation of their activity. For lysosomal proteases proteolytic cleavage of the propeptide is triggered by the acidic pH. By using fluorescence, circular dichroism, and NMR spectroscopy, we show that upon decreasing the pH from 6.5 to 3 the propeptide of cathepsin L loses most of the tertiary structure, but almost none of the secondary structure is lost. Another partially structured intermediate, prone to aggregation, was identified between pH 6.5 and 4. The conformation, populated below pH 4, where the activation of cathepsin L occurs, is not completely unfolded and has the properties of molten globule, including characteristic binding of the 1-anilinonaphthalene-8-sulfonic acid. This pH unfolding of the propeptide parallels a decrease of its affinity for cathepsin L and suggests the mechanism for the acidic zymogen activation. Addition of anionic polysaccharides that activate cathepsin L already at pH 5.5 unfolds the tertiary structure of the propeptide at this pH. Propeptide of human cathepsin L which is able to fold independently represents an evolutionary intermediate in the emergence of novel inhibitors originating from the enzyme proregions.All lysosomal and most other proteases are synthesized in the form of inactive precursors (1, 2). Propeptides are generally located N-terminal to the mature enzyme, and activation of the enzyme is accomplished by cis-or trans-cleavage of the propeptide. Propeptides vary from a few (e.g. trypsin) to more than 200 residues (e.g. cathepsin C). Longer propeptides are generally strong and specific inhibitors of their mature enzymes (3-7). In most cases propeptides are also indispensable for correct folding of the enzymes (8). In some enzymes folding of the mature form is extremely slow, and the propeptide assists in overcoming the kinetic barrier (9), which may also be overcome by physicochemical factors such as high ionic strength in subtilisin, for example (10). Proenzymes are quite often more stable than mature enzymes (11, 12) and can represent a pool of latent enzyme until the activation occurs in the proper conditions. Propeptides are also involved in targeting to specific organelles (13, 14); they can affect posttranslational modification such as glycosylation (15) and mediate interactions with other molecules (16,17). Propeptides can be cleaved either by other proteases or by intra-or intermolecular autocatalysis. pH change is one of the most common environmental parameters responsible for triggering the activation of proteases, occurring in cysteine, aspartic acid, and metalloproteases (1,18,19). Low pH is thought either to increase the susceptibility of the propeptide as a substrate due to the protonation of groups close to the cleavage site or to cause a conformational change in the propeptide or enzyme.Cathepsin L is one of the most active cysteine proteases and accounts for most of the lysosomal cysteine protease activity (20). It has been implicated in a range of processes incl...

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“…A human genomic DNA clone was isolated during efforts to clone cathepsin L that had 88% similarity to the cathepsin L coding sequence and a similar exon arrangement (Bryce et al, 1994). This gene, designated cathepsin L-like gene 1 (CTSLL1), and at least two other related genes (CTSLL2 and 3), were mapped to three different positions on chromosome 10q, and are thus distinct from cathepsins L and V. The three genes were estimated to have evolved during the early primate radiation.…”

Section: (D) Cathepsin V and Other Cathepsin L-like Sequences (I) Promentioning

confidence: 99%

Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

Dickinson

2002

Critical Reviews in Oral Biology & Medicine

158

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Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily "housekeeping" functions in the cell. However, mutations in DPP I have now been shown to underlie Papillon-Lefèvre syndrome and pre-pubertal periodontitis. Other cathepsins are involved in tissue-specific functions such as bone remodeling, but relatively little is known about the functions of several recently discovered enzymes. Collectively, CPs participate in multiple host systems that are active in health and in disease. They are involved in tissue remodeling and turnover of the extracellular matrix, immune system function, and modulation and alteration of cell function. Intracellularly, CPs function in diverse processes including normal protein turnover, antigen and proprotein processing, and apoptosis. Extracellularly, they can contribute directly to the degradation of foreign proteins and the extracellular matrix. However, CPs can also participate in proteolytic cascades that amplify the degradative capacity, potentially leading to pathological damage, and facilitating the penetration of tissues by cancer cells. We know relatively little regarding the role of human CPs in the oral cavity in health or disease. Most studies to date have focused on the potential use of the lysosomal enzymes as markers for periodontal disease activity. Human saliva contains high levels of cystatins, which are potent CP inhibitors. Although these proteins are presumed to serve a protective function, their in vivo targets are unknown, and it remains to be discovered whether they serve to control any human CP activity.

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A Novel Family of Cathepsin L-like (CTSLL) Sequences on Human Chromosome 10q and Related Transcripts

Cited by 14 publications

References 0 publications

Human Paralogs of KIAA0187 Were Created through Independent Pericentromeric-Directed and Chromosome-Specific Duplication Mechanisms

Human Paralogs of KIAA0187 Were Created through Independent Pericentromeric-Directed and Chromosome-Specific Duplication Mechanisms

pH-induced Conformational Transitions of the Propeptide of Human Cathepsin L

Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

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