Soluble Metalloendopeptidases and Neuroendocrine Signaling

Shrimpton, Corie N.; Smith, A. Ian; Lew, Rebecca A.

doi:10.1210/er.2001-0032

Cited by 90 publications

(117 citation statements)

References 163 publications

(162 reference statements)

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“…Modification and Subcellular Localization-TOP activity can be modulated by posttranslational covalent modification (3). The enzyme loses activity in the absence of reducing agents, and this inactivation occurs in part by the formation of disulfide-linked multimers, which appear to lose affinity for substrate (35,37).…”

Section: Resultsmentioning

confidence: 99%

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Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization

Ray¹,

Hines²,

Coll-Rodriguez

et al. 2004

Journal of Biological Chemistry

108

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Thimet oligopeptidase (TOP) is a zinc metallopeptidase that metabolizes a number of bioactive peptides and degrades peptides released by the proteasome, limiting antigenic presentation by MHC class I molecules. We present the crystal structure of human TOP at 2.0-Å resolution. The active site is located at the base of a deep channel that runs the length of the elongated molecule, an overall fold first seen in the closely related metallopeptidase neurolysin. Comparison of the two related structures indicates hinge-like flexibility and identifies elements near one end of the channel that adopt different conformations. Relatively few of the sequence differences between TOP and neurolysin map to the proposed substrate-binding site, and four of these variable residues may account for differences in substrate specificity. In addition, a loop segment (residues 599 -611) in TOP differs in conformation and degree of order from the corresponding neurolysin loop, suggesting it may also play a role in activity differences. Cysteines thought to mediate covalent oligomerization of rat TOP, which can inactivate the enzyme, are found to be surface-accessible in the human enzyme, and additional cysteines (residues 321,350, and 644) may also mediate multimerization in the human homolog. Disorder in the N terminus of TOP indicates it may be involved in subcellular localization, but a potential nuclear import element is found to be part of a helix and, therefore, unlikely to be involved in transport. A large acidic patch on the surface could potentially mediate a protein-protein interaction, possibly through formation of a covalent linkage.Thimet oligopeptidase (TOP, 1 3.4.24.15) is a 77-kDa zinc metalloendopeptidase that bears the His-Glu-Xaa-Xaa-His (HEXXH) active site sequence motif characteristic of a large superfamily of metallopeptidases (1-4). It is widely distributed in mammalian tissues with the highest expression levels in the brain, pituitary gland, and testis (5-8). TOP is present in different subcellular locations depending on cell type, with reports of secreted and cytosolic forms (5-16), membrane association (5-7, 17, 18), and nuclear localization (7,12,14). Consistent with its broad tissue and subcellular compartment distribution, TOP appears to play a variety of physiological roles. It has been implicated in the metabolism of a number of small peptides active in the central nervous system and the periphery including neurotensin, bradykinin, somatostatin, opioids, and angiotensin I (4, 6, 9, 16, 19 -26). In addition, recent reports demonstrate that TOP is primarily responsible for degrading peptides released from proteasomes, thereby limiting the extent of antigen presentation by MHC class I molecules (27-29). TOP has also been linked to amyloid precursor protein processing (30), and it promotes increased degradation of the A␤ peptide, a key component of amyloid plaques in Alzheimer's disease (31). Expression of TOP activity is regulated at the level of transcription (32-34), but activity may also be regulated by po...

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Section: Resultsmentioning

confidence: 99%

“…Thimet oligopeptidase (TOP, 1 3.4.24.15) is a 77-kDa zinc metalloendopeptidase that bears the His-Glu-Xaa-Xaa-His (HEXXH) active site sequence motif characteristic of a large superfamily of metallopeptidases (1)(2)(3)(4). It is widely distributed in mammalian tissues with the highest expression levels in the brain, pituitary gland, and testis (5)(6)(7)(8).…”

mentioning

confidence: 99%

Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization

Ray¹,

Hines²,

Coll-Rodriguez

et al. 2004

Journal of Biological Chemistry

108

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“…Moreover, in the case of short peptides, the activity of specific peptidases (like many membrane, blood, or central nervous system metallo-oligopeptidases) (19), which are selectively active on short sequences, could be prevented by the mass increase and steric hindrance of MAPs. This possibility seems to be supported by the reported results, indicating a higher general stability of MAPs to blood and brain proteases than to trypsin and chymotrypsin.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Peptides in the Form of Dendrimers Become Resistant to Protease Activity

Bracci

Falciani

Lelli

et al. 2003

Journal of Biological Chemistry

155

162

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In previous papers, we observed that dendrimers of peptide mimotopes of the nicotinic receptor ligand site are strong antidotes against the lethality of the nicotinic receptor ligand ␣-bungarotoxin. Although their in vitro activity is identical to that of dendrimers, the corresponding monomeric peptide mimotopes are not effective in vivo. Because the higher in vivo efficiency of dendrimers could not in this case be related to polyvalent interaction, the stability to blood protease activity of monomeric versus tetrabranched dendrimeric mimotope peptides was compared here by incubating three different mimotopes with human plasma and serum. Unmodified peptides and cleaved sequences were followed by high pressure liquid chromatography and mass spectrometry. Tetrabranched peptides were shown to be much more stable in plasma and also in serum. To assess the notable stability of multimeric peptides, different bioactive neuropeptides, including enkephalins, neurotensin and nociceptin, were synthesized in monomeric and tetrabranched forms and incubated with human plasma and serum and with rat brain membrane extracts. All the tetrabranched neuropeptides fully retained biological activity and generally showed much greater stability to blood and brain protease activity. Some tetrabranched peptides were also resistant to trypsin and chymotrypsin. Our findings provide new insights into the possible therapeutic use of bioactive peptides.Hundreds of peptides with potential therapeutic activities have been identified. These include naturally occurring peptide hormones and neurotransmitters, which influence and control series of vital functions, such as cell proliferation, tissue development, metabolism, immune defense, perception of pain, reproduction, behavior, and blood pressure. Selective agonists or antagonists of these natural peptides are extremely useful for the investigation of peptidergic systems and are also potential therapeutic agents (1). Moreover, several peptide fragments or mimotopes derived from potential therapeutic proteins show promising biological activity (2).However, the use of peptides as therapeutic drugs has largely been limited by their short half-life in vivo. Because peptides are mainly broken down by proteases and peptidases, peptide delivery is the bottleneck in the development of new peptide drugs. To increase peptide half-life, many strategies involving different levels of chemical modification are possible (3, 4). The introduction of D-amino acids, or pseudo amino acids, and peptide cyclization are the most common strategies to increase peptide stability. However, these modifications may profoundly alter peptide activity. Alternatively, peptidomimetic molecules can be developed by the synthesis of conformationally restricted compounds, in which the peptide is locally or globally constrained in order to reproduce the active conformation. The resulting structures are mostly non-peptide molecules, more resistant to degrading enzymes.In general, peptide molecules have the advantage of good specifici...

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“…Human proteins included in M3 family are the soluble metallopeptidases neurolysin and thimet oligopeptidase (TOP), which reveal similar biological and biochemical features, and mitochondrial-processing-peptidase (MIP) ( Table 1) (see for review Shrimpton et al, 2002;Ferro et al, 2004). Although neurolysin and TOP are well characterized biochemically, their physiopathological role has yet to be established.…”

Section: M3 Familymentioning

confidence: 99%

“…In particular, several studies indicate an involvement of neurolysin and TOP in neurotensin degradation (by exerting a broad range of endocrine and cardiovascular effect, such as hypotension, analgesia and hypothermia) and in bradykinin degradation, postulating a direct involvement in blood pressure regulation (Chabry et al, 1990;Checler et al, 1995;Davis et al, 1992;Genden and Molineaux, 1991;Kadonosono et al, 2007;Norman et al, 2003). Additionally TOP inactivates opioids and the gonadotrophin-releasing hormone, suggesting a putative role in the modulation of nociception and reproductive physiology (Cyr et al, 2010;Kest et al, 1991;Shrimpton et al, 2002). ligands, tumor necrosis factor a (TNF-a), cell adhesion molecules like CD44 and cadherins (Blobel, 2005;Nagano et al, 2004;Reiss et al, 2005).…”

Section: M3 Familymentioning

confidence: 99%

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Sbardella

Fasciglione

Gioia

et al. 2012

Molecular Aspects of Medicine

208

212

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a b s t r a c tHuman matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn 2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes.

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Soluble Metalloendopeptidases and Neuroendocrine Signaling

Cited by 90 publications

References 163 publications

Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization

Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization

Synthetic Peptides in the Form of Dendrimers Become Resistant to Protease Activity

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

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