Elastin Degradation by Cathepsin V Requires Two Exosites

Du, Xin; Chen, Nelson L.H.; Wong, Audrey; Craik, Charles S.; Brὂmme, Dieter

doi:10.1074/jbc.m113.510008

Cited by 39 publications

(26 citation statements)

References 32 publications

(43 reference statements)

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“…It has come forth that apart from tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S, which promotes neovascularization and tumor growth [39]. Cathepsin V (or L2), an elastase, is involved in cancer invasion and metastasis as well [40]. Cathepsins K, L, S, F, V, and B possess elastolytic activities and are reported to be responsible for the stiffening of arteries in atherosclerosis [41,42].…”

Section: Types Of Cathepsins and Their Functional Specificitiesmentioning

confidence: 99%

Cathepsins: Proteases that are vital for survival but can also be fatal

Patel

Homaei

El‐Seedi

et al. 2018

Biomedicine & Pharmacotherapy

160

108

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The state of enzymes in the human body determines the normal physiology or pathology, so all the six classes of enzymes are crucial. Proteases, the hydrolases, can be of several types based on the nucleophilic amino acid or the metal cofactor needed for their activity. Cathepsins are proteases with serine, cysteine, or aspartic acid residues as the nucleophiles, which are vital for digestion, coagulation, immune response, adipogenesis, hormone liberation, peptide synthesis, among a litany of other functions. But inflammatory state radically affects their normal roles. Released from the lysosomes, they degrade extracellular matrix proteins such as collagen and elastin, mediating parasite infection, autoimmune diseases, tumor metastasis, cardiovascular issues, and neural degeneration, among other health hazards. Over the years, the different types and isoforms of cathepsin, their optimal pH and functions have been studied, yet much information is still elusive. By taming and harnessing cathepsins, by inhibitors and judicious lifestyle, a gamut of malignancies can be resolved. This review discusses these aspects, which can be of clinical relevance.

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Section: Types Of Cathepsins and Their Functional Specificitiesmentioning

confidence: 99%

Cathepsins: Proteases that are vital for survival but can also be fatal

Patel

Homaei

El‐Seedi

et al. 2018

Biomedicine & Pharmacotherapy

160

108

View full text Add to dashboard Cite

show abstract

“…The exosite centered at 42 RRR 44 shares characteristics with exosites identified in proteases, including thrombin (60, 61), the cathepsin family (62,63), and ␤-secretase (BACE) (64), as well as in kinases (65) that enable recruitment of protein substrates. Exosite compositions in various enzymes differ based on their intended substrates.…”

Section: Caspase-6 Exosite For Substrate Recognitionmentioning

confidence: 99%

Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis

MacPherson

Mills

Ondrechen

et al. 2019

Journal of Biological Chemistry

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Edited by Norma M. AllewellCaspases are cysteine-aspartic proteases involved in the regulation of programmed cell death (apoptosis) and a number of other biological processes. Despite overall similarities in structure and active-site composition, caspases show striking selectivity for particular protein substrates. Exosites are emerging as one of the mechanisms by which caspases can recruit, engage, and orient these substrates for proper hydrolysis. Following computational analyses and database searches for candidate exosites, we utilized site-directed mutagenesis to identify a new exosite in caspase-6 at the hinge between the disordered N-terminal domain (NTD), residues 23-45, and core of the caspase-6 structure. We observed that substitutions of the tri-arginine patch Arg-42-Arg-44 or the R44K cancer-associated mutation in caspase-6 markedly alter its rates of protein substrate hydrolysis. Notably, turnover of protein substrates but not of short peptide substrates was affected by these exosite alterations, underscoring the importance of this region for protein substrate recruitment. Hydrogen-deuterium exchange MS-mediated interrogation of the intrinsic dynamics of these enzymes suggested the presence of a substrate-binding platform encompassed by the NTD and the 240's region (containing residues 236 -246), which serves as a general exosite for caspase-6specific substrate recruitment. In summary, we have identified an exosite on caspase-6 that is critical for protein substrate recognition and turnover and therefore highly relevant for diseases such as cancer in which caspase-6 -mediated apoptosis is often disrupted, and in neurodegeneration in which caspase-6 plays a central role.

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“…Mouse cathepsin L is homologous to human cathepsin V based on its amino acid sequence homology and expression pattern (9). Therefore, translation of our results into humans would focus on the role of human cathepsin V (9,10,25). Macrophages have the highest cathepsin expression.…”

Section: Cathepsin L Activity Assaymentioning

confidence: 99%

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

Cai

Zhong

et al. 2017

Mol Med

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The inflammatory pathways that drive the development of intimal hyperplasia (IH) following arterial injury are not fully understood. We hypothesized that the lysosomal cysteine protease cathepsin L activates processes leading to IH after arterial injury. Using a mouse model of wire-induced carotid artery injury, we showed that cathepsin L activity peaks at d 7 and remains elevated for 28 d. Genetic deletion of cathepsin L prevented IH and monocyte recruitment in the carotid wall. The injury-induced increases in cathepsin L mRNA and activity were mitigated in mice with myeloid-specific deletion of toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88). We further discovered that the HIV protease inhibitor saquinavir (SQV), which is known to block recombinant mouse cathepsin L activity in vitro, prevented IH after arterial injury. SQV also suppressed LPS (TLR4 agonist)-induced monocyte adhesion to endothelial monolayers. These findings establish cathepsin L as a critical regulator of the inflammation that leads to IH and that the TLR4-MyD88 pathway in myeloid lineages regulates cathepsin L expression in the vessel wall following wire injury. The Food and Drug Administration-approved drug SQV blocks IH though mechanisms that may include the suppression of cathepsin L.

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Elastin Degradation by Cathepsin V Requires Two Exosites

Cited by 39 publications

References 32 publications

Cathepsins: Proteases that are vital for survival but can also be fatal

Cathepsins: Proteases that are vital for survival but can also be fatal

Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

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