-
Acta Crystallographica. Section D,... Nov 2022The horseshoe crab Limulus polyphemus is one of few extant Limulus species, which date back to ∼250 million years ago under the conservation of a common Bauplan...
The horseshoe crab Limulus polyphemus is one of few extant Limulus species, which date back to ∼250 million years ago under the conservation of a common Bauplan documented by fossil records. It possesses the only proteolytic blood-coagulation and innate immunity system outside vertebrates and is a model organism for the study of the evolution and function of peptidases. The astacins are a family of metallopeptidases that share a central ∼200-residue catalytic domain (CD), which is found in >1000 species across holozoans and, sporadically, bacteria. Here, the zymogen of an astacin from L. polyphemus was crystallized and its structure was solved. A 34-residue, mostly unstructured pro-peptide (PP) traverses, and thus blocks, the active-site cleft of the CD in the opposite direction to a substrate. A central `PP motif' (F-E-G-D-I) adopts a loop structure which positions Asp38 to bind the catalytic metal, replacing the solvent molecule required for catalysis in the mature enzyme according to an `aspartate-switch' mechanism. Maturation cleavage of the PP liberates the cleft and causes the rearrangement of an `activation segment'. Moreover, the mature N-terminus is repositioned to penetrate the CD moiety and is anchored to a buried `family-specific' glutamate. Overall, this mechanism of latency is reminiscent of that of the other three astacins with known zymogenic and mature structures, namely crayfish astacin, human meprin β and bacterial myroilysin, but each shows specific structural characteristics. Remarkably, myroilysin lacks the PP motif and employs a cysteine instead of the aspartate to block the catalytic metal.
Topics: Animals; Humans; Aspartic Acid; Metalloproteases; Enzyme Precursors; Catalytic Domain; Peptide Hydrolases
PubMed: 36322418
DOI: 10.1107/S2059798322009688 -
Biochimica Et Biophysica Acta.... Jan 2022The metalloproteinase meprin β plays an important role during collagen I deposition in the skin, mucus detachment in the small intestine and also regulates the... (Review)
Review
The metalloproteinase meprin β plays an important role during collagen I deposition in the skin, mucus detachment in the small intestine and also regulates the abundance of different cell surface proteins such as the interleukin-6 receptor (IL-6R), the triggering receptor expressed on myeloid cells 2 (TREM2), the cluster of differentiation 99 (CD99), the amyloid precursor protein (APP) and the cluster of differentiation 109 (CD109). With that, regulatory mechanisms that control meprin β activity and regulate its release from the cell surface to enable access to distant substrates are increasingly important. Here, we will summarize factors that alternate meprin β activity and thereby regulate its proteolytic activity on the cell surface or in the supernatant. We will also discuss cleavage of the IL-6R and TREM2 on the cell surface and compare it to CD109. CD109, as a substrate of meprin β, is cleaved within the protein core, thereby releasing defined fragments from the cell surface. At last, we will also summarize the role of proteases in general and meprin β in particular in substrate release on extracellular vesicles.
Topics: Animals; Extracellular Vesicles; Humans; Metalloendopeptidases; Proteolysis; Signal Transduction
PubMed: 34626678
DOI: 10.1016/j.bbamcr.2021.119136 -
The New Phytologist Aug 2022Plants encode > 100 metalloproteases representing > 19 different protein families. Tools to study this large and diverse class of proteases have not yet been...
Plants encode > 100 metalloproteases representing > 19 different protein families. Tools to study this large and diverse class of proteases have not yet been introduced into plant research. We describe the use of hydroxamate-based photoaffinity probes to explore plant proteomes for metalloproteases. We detected labelling of 23 metalloproteases in leaf extracts of the model plant Arabidopsis thaliana that belong to nine different metalloprotease families and localize to different subcellular compartments. The probes identified several chloroplastic FtsH proteases, vacuolar aspartyl aminopeptidase DAP1, peroxisomal metalloprotease PMX16, extracellular matrix metalloproteases and many cytosolic metalloproteases. We also identified nonproteolytic metallohydrolases involved in the release of auxin and in the urea cycle. Studies on tobacco plants (Nicotiana benthamiana) infected with the bacterial plant pathogen Pseudomonas syringae uncovered the induced labelling of PRp27, a secreted protein with implicated metalloprotease activity. PRp27 overexpression increases resistance, and PRp27 mutants lacking metal binding site are no longer labelled, but still show increased immunity. Collectively, these studies reveal the power of broad-range metalloprotease profiling in plants using hydroxamate-based probes.
Topics: Arabidopsis; Arabidopsis Proteins; Metalloproteases; Metalloproteins; Plant Diseases; Pseudomonas syringae; Nicotiana
PubMed: 35510806
DOI: 10.1111/nph.18200 -
Experimental Eye Research Oct 2017The function of the meibomian gland in the upper and lower eyelids is critical to maintaining homeostasis at the ocular surface. Highly specialized meibocytes within the... (Review)
Review
The function of the meibomian gland in the upper and lower eyelids is critical to maintaining homeostasis at the ocular surface. Highly specialized meibocytes within the gland must differentiate and accumulate intracellular lipid droplets that are released into the tear film following rupture of the cell membrane. Proteases and their inhibitors have been recognized as key players in remodeling extracellular matrices and promoting the normal integrity of glandular tissue. They modulate a wide range of biological processes, such as cell proliferation and differentiation, and can contribute to disease when aberrantly expressed. Deciphering the role of proteolytic activity in the meibomian gland offers an opportunity to gain a more comprehensive and fundamental understanding of the developmental, physiological, and pathological processes associated with this gland.
Topics: Aging; Dry Eye Syndromes; Extracellular Matrix; Humans; Meibomian Glands; Metalloproteases; Peptide Hydrolases; Proteolysis; Sebaceous Glands
PubMed: 28284957
DOI: 10.1016/j.exer.2017.03.001 -
Matrix Biology : Journal of the... 2015Metalloproteases meprin α and meprin β were recently discovered as procollagen proteinases, capable of cleaving off the globular C- and N-terminal prodomains of... (Review)
Review
Metalloproteases meprin α and meprin β were recently discovered as procollagen proteinases, capable of cleaving off the globular C- and N-terminal prodomains of fibrillar collagen type I and type III. This proteolytic process is indeed sufficient to induce collagen fibril assembly as visualized by transmission electron microscopy. The biological relevance was demonstrated with the help of meprin α and meprin β knock-out mice, which exhibit decreased collagen deposition in skin resulting in impaired tensile strength. On the other hand, overexpression of meprin metalloproteases was found under fibrotic conditions in the skin (keloids) and the lung (pulmonary hypertension). Thus, regulation of meprin activity by specific inhibition to reduce collagen maturation might be a suitable approach for the treatment of certain pathological conditions.
Topics: Animals; Collagen Type I; Collagen Type III; Gene Expression Regulation, Enzymologic; Gene Knockout Techniques; Humans; Hypertension, Pulmonary; Keloid; Metalloendopeptidases; Mice; Procollagen; Tensile Strength
PubMed: 25617491
DOI: 10.1016/j.matbio.2015.01.010 -
Microbiology and Immunology Jan 2017Vibrio vulnificus, a gram-negative halophilic estuarine bacterium, is an opportunistic human pathogen that causes rapidly progressive fatal septicemia and necrotizing... (Review)
Review
Vibrio vulnificus, a gram-negative halophilic estuarine bacterium, is an opportunistic human pathogen that causes rapidly progressive fatal septicemia and necrotizing wound infection. This species also causes hemorrhagic septicemia called vibriosis in cultured eels. It has been proposed that a range of virulence factors play roles in pathogenesis during human and/or eel infection. Among these factors, a metalloprotease (V. vulnificus protease [VVP]) and a cytolytic toxin (V. vulnificus hemolysin [VVH]) are of significant importance. VVP elicits the characteristic edematous and hemorrhagic skin damage, whereas VVH exhibits powerful hemolytic and cytolytic activities and contributes to bacterial invasion from the intestine to the blood stream. In addition, a few V. vulnificus strains isolated from diseased eels have recently been found to produce a serine protease designated as V. vulnificus serine protease (VvsA) instead of VVP. Similarly to VVP, VvsA may possess various toxic activities such as collagenolytic, cytotoxic and edema-forming activity. In this review, regulation of V. vulnificus VVP, VVH and VvsA is clarified in terms of expression at the mRNA and protein levels. The explanation is given on the basis of the quorum sensing system, which is dependent on bacterial cell density. In addition, the roles of environmental factors and global regulators, such as histone-like nucleoid structuring protein, cyclic adeno monophosphate receptor protein, RpoS, HlyU, Fur, ToxRS, AphB and LeuO, in this regulation are outlined. The cumulative impact of these regulatory systems on the pathogenicity of V. vulnificus is here delineated.
Topics: Animals; Bacterial Proteins; Hemolysin Proteins; Humans; Metalloendopeptidases; Metalloproteases; RNA, Messenger; Vibrio vulnificus; Virulence Factors
PubMed: 28111826
DOI: 10.1111/1348-0421.12465 -
Human Cell Nov 2022Endothelial dysfunction is one of the key cornerstone complications of emerging and re-emerging viruses which lead to vascular leakage and a high mortality rate. The... (Review)
Review
Endothelial dysfunction is one of the key cornerstone complications of emerging and re-emerging viruses which lead to vascular leakage and a high mortality rate. The mechanism that regulates the origin of endothelial dysregulation is not completely elucidated. Currently, there are no potential pharmacological treatments and curable management for such diseases. In this sense, mesenchymal stromal/stem cells (MSCs) has been emerging to be a promising therapeutic strategy in restoring endothelial barrier function in various lung disease, including ALI and ARDS. The mechanism of the role of MSCs in restoring endothelial integrity among single-strand RNA (ssRNA) viruses that target endothelial cells remains elusive. Thus, we have discussed the therapeutic role of MSCs in restoring vascular integrity by (i) inhibiting the metalloprotease activity thereby preventing the cleavage of tight junction proteins, which are essential for maintaining membrane integrity (ii) possessing antioxidant properties which neutralize the excessive ROS production due to virus infection and its associated hyper host immune response (iii) modulating micro RNAs that regulate the endothelial activation and its integrity by downregulating the inflammatory response during ssRNA infection.
Topics: Antioxidants; Endothelial Cells; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Metalloproteases; RNA; Reactive Oxygen Species; Tight Junction Proteins; Virus Diseases
PubMed: 36068397
DOI: 10.1007/s13577-022-00785-3 -
The Journal of Biological Chemistry Dec 2023Increasing evidence suggests that aberrant regulation of sortilin ectodomain shedding can contribute to amyloid-β pathology and frontotemporal dementia, although the...
Increasing evidence suggests that aberrant regulation of sortilin ectodomain shedding can contribute to amyloid-β pathology and frontotemporal dementia, although the mechanism by which this occurs has not been elucidated. Here, we probed for novel binding partners of sortilin using multiple and complementary approaches and identified two proteins of the neuron-specific gene (NSG) family, NSG1 and NSG2, that physically interact and colocalize with sortilin. We show both NSG1 and NSG2 induce subcellular redistribution of sortilin to NSG1- and NSG2-enriched compartments. However, using cell surface biotinylation, we found only NSG1 reduced sortilin cell surface expression, which caused significant reductions in uptake of progranulin, a molecular determinant for frontotemporal dementia. In contrast, we demonstrate NSG2 has no effect on sortilin cell surface abundance or progranulin uptake, suggesting specificity for NSG1 in the regulation of sortilin cell surface expression. Using metalloproteinase inhibitors and A disintegrin and metalloproteinase 10 KO cells, we further show that NSG1-dependent reduction of cell surface sortilin occurred via proteolytic processing by A disintegrin and metalloproteinase 10 with a concomitant increase in shedding of sortilin ectodomain to the extracellular space. This represents a novel regulatory mechanism for sortilin ectodomain shedding that is regulated in a neuron-specific manner. Furthermore, this finding has implications for the development of strategies for brain-specific regulation of sortilin and possibly sortilin-driven pathologies.
Topics: Adaptor Proteins, Vesicular Transport; Biotinylation; Brain; Carrier Proteins; Disintegrins; Frontotemporal Dementia; Metalloproteases; Nerve Tissue Proteins; Neurons; Progranulins; Protein Binding; Proteolysis; Cell Membrane; Amyloid beta-Peptides
PubMed: 37949230
DOI: 10.1016/j.jbc.2023.105446 -
Toxins Jul 2022We previously demonstrated that jellyfish venom metalloproteinases (JVMPs) play a key role in the toxicities induced by venom (NnV), including dermotoxicity,...
We previously demonstrated that jellyfish venom metalloproteinases (JVMPs) play a key role in the toxicities induced by venom (NnV), including dermotoxicity, cytotoxicity, and lethality. In this study, we identified two full-length JVMP cDNA and genomic DNA sequences: JVMP17-1 and JVMP17-2. The full-length cDNA of JVMP17-1 and 17-2 contains 1614 and 1578 nucleotides (nt) that encode 536 and 525 amino acids, respectively. Putative peptidoglycan (PG) binding, zinc-dependent metalloproteinase, and hemopexin domains were identified. BLAST analysis of JVMP17-1 showed 42, 41, 37, and 37% identity with , , and venom metalloproteinases, respectively. JVMP17-2 shared 38 and 36% identity with and . , respectively. Alignment results of JVMP17-1 and 17-2 with other metalloproteinases suggest that the PG domain, the tissue inhibitor of metalloproteinase (TIMP)-binding surfaces, active sites, and metal (ion)-binding sites are highly conserved. The present study reports the gene cloning of metalloproteinase enzymes from jellyfish species for the first time. We hope these results can expand our knowledge of metalloproteinase components and their roles in the pathogenesis of jellyfish envenomation.
Topics: Animals; Cloning, Molecular; Cnidaria; Cnidarian Venoms; DNA, Complementary; Metalloproteases; Scyphozoa
PubMed: 36006181
DOI: 10.3390/toxins14080519 -
Cell Adhesion & Migration Dec 2020The ADAMs family belongs to the transmembrane protein superfamily of zinc-dependent metalloproteases, which consists of multiple domains. These domains have independent... (Review)
Review
The ADAMs family belongs to the transmembrane protein superfamily of zinc-dependent metalloproteases, which consists of multiple domains. These domains have independent but complementary functions that enable them to participate in multiple biological processes. Among them, ADAM9 can not only participate in the degradation of extracellular matrix as a metalloprotease, but also mediate tumor cell adhesion through its deintegrin domain, which is closely related to tumor invasion and metastasis. It is widely expressed in a variety of tumor cells and can affect the proliferation, invasion and metastasis of related cancer cells. We provide our views on current progress, its increasing importance as a strategic treatment goal, and our vision for the future of ADAM9.
Topics: ADAM Proteins; Evolution, Molecular; Gene Expression Regulation, Neoplastic; Humans; Neoplasms
PubMed: 32875951
DOI: 10.1080/19336918.2020.1817251