Charge-Triggered Membrane Insertion of Matrix Metalloproteinase-7, Supporter of Innate Immunity and Tumors

Prior, Stephen H.; Fulcher, Yan G.; Koppisetti, Rama K.; Jurkevich, Alexander; Doren, Steven R. Van

doi:10.1016/j.str.2015.08.013

Cited by 25 publications

(40 citation statements)

References 54 publications

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“…The cold impeding the ingress of MMP-12 suggests endocytosis [67]. Similarly, proMMP-7 binds the plasma membrane of colon cancer cells, is internalized, and accumulates in cytoplasmic vesicles within 5 min after addition [50]. Since GSL, SM, and PC are enriched on the luminal face of endosomes [25], MMPs are likely to meet these lipids during endocytosis.…”

Section: Influences Of Peripheral Membrane Interactions On Mmp Actmentioning

confidence: 99%

“…The internalization of soluble MMP-7 and -12 within 5 min [50, 67] is faster than the internalization of transmembrane-anchored MT1-MMP in 30 to 45 min [83], GPI-anchored MT4-MMP in 45 to 60 min [84], or GPI-anchored MT6-MMP which is also slow [85]. Deletion of the transmembrane helical anchor of MT1-MMP is disruptive to trafficking and recycling [83].…”

Section: Influences Of Peripheral Membrane Interactions On Mmp Actmentioning

confidence: 99%

“…Binding of CS was confirmed, but so was HSPG binding, in an independent study analyzing high affinity binding of MMP-7 (matrilysin) to cancer cells [23]. Anionic lipids are required for the high affinity of MMP-7 for vesicles [49, 50]. This article considers a few functional implications of peripheral interactions of MMPs with cell membrane bilayers, the interfaces of MMP catalytic and hemopexin-like (HPX) domains for lipid bilayers, and possibilities for lipid bilayer interactions with additional soluble MMP domains.…”

Section: Introductionmentioning

confidence: 99%

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Peripheral membrane associations of matrix metalloproteinases

Doren

Marcink

Koppisetti

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Water soluble matrix metalloproteinases (MMPs) have been regarded as diffusing freely in the extracellular matrix. Yet multiple MMPs are also observed at cell surfaces. Their membrane-proximal activities include sheddase activities, collagenolysis, bacterial killing, and intracellular trafficking reaching as far as the nucleus. The catalytic domains of MMP-7 and MMP-12 bind bilayers peripherally, each in two different orientations, by presenting positive charges and a few hydrophobic groups to the surface. Related peripheral membrane associations are predicted for other soluble MMPs. The peripheral membrane associations may support pericellular proteolysis and endocytosis. The isolated soluble domains of MT1-MMP can also associate with membranes. NMR assays suggest transient association of the hemopexin-like domains of MT1-MMP and MMP-12 with lipid bilayers. Peripheral association of soluble MMP domains with bilayers or heparin sulfate proteoglycans probably concentrates them near the membrane. This could increase the probability of forming complexes with membrane-associated proteins, such as those targeted for proteolysis.

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Section: Influences Of Peripheral Membrane Interactions On Mmp Actmentioning

confidence: 99%

Section: Influences Of Peripheral Membrane Interactions On Mmp Actmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peripheral membrane associations of matrix metalloproteinases

Doren

Marcink

Koppisetti

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…This reinforces the hypothesis that this loop may be important in the molecular recognition of fibrillar substrates en route to the active site. The II-III loop is also critically important for the molecular recognition of membrane bilayers (39,40) and a receptor (72). These precedents and the PREs from spin-labeled triple-helical peptides encompassing the II-III loop may be consistent with the possibility of a functional role in initial associations with collagen triple helix.…”

Section: Encounter Complexes and Implicationsmentioning

confidence: 70%

“…These 1 H NMR line broadenings are measured as paramagnetic relaxation enhancements (PREs) most reliably as transverse relaxation rate constants, ⌫ 2 (35). The insights from PREs into complexes of lower affinity (35) have been exploited to characterize the structures of mixtures of specific and nonspecific protein complexes with DNA (33), proteins (34), redox protein partners (32,37,38), and bilayer mimics (39,40). Synthesis of a nitroxide-containing artificial amino acid into key locations within a triple-helical peptide model of collagens I-III enabled structural capture of its transient complex with a domain of MT1-MMP (41).…”

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confidence: 99%

Path to Collagenolysis

Prior

Byrne

Tokmina‐Roszyk

et al. 2016

Journal of Biological Chemistry

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Collagenolysis is essential in extracellular matrix homeostasis, but its structural basis has long been shrouded in mystery. We have developed a novel docking strategy guided by paramagnetic NMR that positions a triple-helical collagen V mimic (synthesized with nitroxide spin labels) in the active site of the catalytic domain of matrix metalloproteinase-12 (MMP-12 or macrophage metalloelastase) primed for catalysis. The collagenolytically productive complex forms by utilizing seven distinct subsites that traverse the entire length of the active site. These subsites bury ϳ1,080 Å 2 of surface area, over half of which is contributed by the trailing strand of the synthetic collagen V mimic, which also appears to ligate the catalytic zinc through the glycine carbonyl oxygen of its scissile GϳVV triplet. Notably, the middle strand also occupies the full length of the active site where it contributes extensive interfacial contacts with five subsites. This work identifies, for the first time, the productive and specific interactions of a collagen triple helix with an MMP catalytic site. The results uniquely demonstrate that the active site of the MMPs is wide enough to accommodate two strands from collagen triple helices. Paramagnetic relaxation enhancements also reveal an extensive array of encounter complexes that form over a large part of the catalytic domain. These transient complexes could possibly facilitate the formation of collagenolytically active complexes via directional Brownian tumbling.Collagens comprise around 30% of the protein mass of the body (1) and resist general proteolysis. Matrix metalloproteinases (MMPs) 2 degrade collagen during cancer cell migration (2), angiogenesis (3, 4), destabilization of atherosclerotic plaques (5), and arthritis (6) and after myocardial infarction (7). For instance, plaques contain a collagen-rich cap and are sensitive to MMP-12 secreted by macrophages that makes them more vulnerable to rupture, precipitating myocardial infarction, or stroke (8).Collagen fibrils are bundles of staggered triple helices. Each triple helix comprises three extended strands twisted into a right-handed superhelix with hydrogen bonding between chains (9). Each collagen chain is a long series of GXY triplets in which the glycine is in the interior, X is often proline, and Y is often a stabilizing 4-hydroxyproline (Hyp). Because each chain is offset by one residue, the chains have been named leading, middle, and trailing (10). Lack of Pro and Hyp in four GXY triplets on the C-terminal side of the MMP scissile bond in interstitial collagens (types I, II, and III) was proposed to loosen the triple helix (1); this was later observed as 10-fold symmetry (11).Protease substrates are labeled by increasing distance from the scissile peptide bond with a prime indicating the C-terminal side: P 4 -P 3 -P-P 1 ϳP 1 Ј-P 2 Ј-P 3 Ј-P 4 Ј where ϳ denotes the scissile peptide bond. We refer to the residues on the N-terminal side of the scissile bond as "unprimed" and those on the C-terminal side as "primed." The...

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Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

Radisky

Raeeszadeh‐Sarmazdeh

Radisky

2017

J of Cellular Biochemistry

124

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Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that cleave nearly all components of the extracellular matrix as well as many other soluble and cell-associated proteins. MMPs have been implicated in normal physiological processes, including development, and in the acquisition and progression of the malignant phenotype. Disappointing results from a series of clinical trials testing small molecule, broad spectrum MMP inhibitors as cancer therapeutics led to a re-evaluation of how MMPs function in the tumor microenvironment, and ongoing research continues to reveal that these proteins play complex roles in cancer development and progression. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the MMP family and its biological regulators, the tissue inhibitors of metalloproteinases (TIMPs). We then summarize recent research from model systems that elucidate how specific MMPs drive the malignant phenotype of breast cancer cells, including acquisition of cancer stem cell features and induction of the epithelial-mesenchymal transition, and we also outline clinical studies that implicate specific MMPs in breast cancer outcomes. We conclude by discussing ongoing strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold.

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Charge-Triggered Membrane Insertion of Matrix Metalloproteinase-7, Supporter of Innate Immunity and Tumors

Cited by 25 publications

References 54 publications

Peripheral membrane associations of matrix metalloproteinases

Peripheral membrane associations of matrix metalloproteinases

Path to Collagenolysis

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

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