Functional Comparison of Two Human Monocyte Chemotactic Protein-2 Isoforms, Role of the Amino-Terminal Pyroglutamic Acid and Processing by CD26/Dipeptidyl Peptidase IV

Coillie, van E; Proost, Paul; Aelst, Van; Struyf, Sofie; Polfliet, Magali; Meester, De; Harvey, David J.; Damme, van J; Opdenakker, Ghislain

doi:10.1021/bi980497d

Cited by 142 publications

(133 citation statements)

References 48 publications

(79 reference statements)

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“…Previously, we detected a larger MCP-2 transcript in testis tissue; this was caused by extension of the mRNA at the 5Ј-end [19]. To investigate whether the larger MCP-2 transcripts in E 6 SM cells were also 5Ј-extended, we hybridized the Northern blot ( Fig.…”

Section: Analysis Of the Extended Mcp-2 Transcripts In Diploid Fibrobmentioning

confidence: 98%

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Transcriptional control of the human MCP-2 gene promoter by IFN-γ and IL-1β in connective tissue cells

Coillie

Aelst

Fiten

et al. 1999

Journal of Leukocyte Biology

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Section: Analysis Of the Extended Mcp-2 Transcripts In Diploid Fibrobmentioning

confidence: 98%

“…Therefore, the MCP-2 gene was first cloned [16] from the CC chemokine YAC contig on the human chromosomal region 17q11.2 [17]. Thereafter, a full-size ϳ900-bp MCP-2 cDNA was isolated from a bone marrow cDNA library [18] and a 5Ј-end-extended MCP-2 cDNA variant was cloned from human testis tissue [19].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional control of the human MCP-2 gene promoter by IFN-γ and IL-1β in connective tissue cells

Coillie

Aelst

Fiten

et al. 1999

Journal of Leukocyte Biology

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“…Other chemokines, i.e. the monocyte chemotactic protein-1, -2, and -3 were found to be protected from CD26/DPP IV-processing by an NH 2 -terminal pyroglutamic acid (9,26). Based on the MDC sequence, containing a penultimate Pro, and on the observation that different natural NH 2 -terminally truncated MDC forms have been isolated (17), the CC chemokine MDC was investigated as a candidate substrate for CD26/DPP IV.…”

Section: Fig 1 Kinetics Of the Nh 2 -Terminal Truncation Of Mdc(1-9)mentioning

confidence: 99%

Truncation of Macrophage-derived Chemokine by CD26/ Dipeptidyl-Peptidase IV beyond Its Predicted Cleavage Site Affects Chemotactic Activity and CC Chemokine Receptor 4 Interaction

Proost¹,

Struyf²,

Schols

et al. 1999

Journal of Biological Chemistry

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150

108

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The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) and chemokines are known key players in immunological processes. Surprisingly, CD26/DPP IV not only removed the expected Gly 1 -Pro 2 dipeptide from the NH 2 terminus of macrophage-derived chemokine (MDC) but subsequently also the Tyr 3 -Gly 4 dipeptide, generating MDC(5-69). This second cleavage after a Gly residue demonstrated that the substrate specificity of this protease is less restricted than anticipated. The unusual processing of MDC by CD26/DPP IV was confirmed on the synthetic peptides GPYGANMED (MDC(1-9)) and YGANMED (MDC(3-9)). Compared with intact MDC(1-69), CD26/DPP IV-processed MDC(5-69) had reduced chemotactic activity on lymphocytes and monocyte-derived dendritic cells, showed impaired mobilization of intracellular Ca 2؉ through CC chemokine receptor 4 (CCR4), and was unable to desensitize for MDC-induced Ca 2؉ -responses in CCR4 transfectants. However, MDC(5-69) remained equally chemotactic as intact MDC(1-69) on monocytes. In contrast to the reduced binding to lymphocytes and CCR4 transfectants, MDC(5-69) retained its binding properties to monocytes and its anti-HIV-1 activity. Thus, NH 2 -terminal truncation of MDC by CD26/DPP IV has profound biological consequences and may be an important regulatory mechanism during the migration of Th2 lymphocytes and dendritic cells to germinal centers and to sites of inflammation.

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“…These regulatory peptides require the N-terminal pGlu to develop the proper conformation for binding to their receptors and͞or to protect the N termini of the peptides from exopeptidase degradation (1,2). Previously, this Nterminal cyclization reaction was thought to proceed spontaneously, until the glutaminyl cyclases (QCs) were identified as catalysts that are responsible for this posttranslational modification (3,4).…”

mentioning

confidence: 99%

Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation

Huang

Liu

Cheng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

105

120

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N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The aberrant formation of pGlu may be related to several pathological processes, such as osteoporosis and amyloidotic diseases. This N-terminal cyclization reaction, once thought to proceed spontaneously, is greatly facilitated by the enzyme glutaminyl cyclase (QC). To probe this important but poorly understood modification, we present here the structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors. The structure reveals an ␣͞␤ scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The relatively closed active site displays alternate conformations due to the different indole orientations of Trp-207, resulting in two substrate (glutamine t-butyl ester)-binding modes. The single zinc ion in the active site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors. Together with structural and kinetic analyses of several active-site-mutant enzymes, a catalysis mechanism of the formation of protein N-terminal pGlu is proposed. Our results provide a structural basis for the rational design of inhibitors against QC-associated disorders.crystallography ͉ intramolecular cyclization ͉ posttranslational modification ͉ Alzheimer's disease ͉ aminopeptidase N -terminal pyroglutamate (pGlu) formation from its glutaminyl precursor is an important posttranslational or cotranslational event in the processing of numerous bioactive neuropeptides, hormones, and cytokines during their maturation in the secretory pathway. These regulatory peptides require the N-terminal pGlu to develop the proper conformation for binding to their receptors and͞or to protect the N termini of the peptides from exopeptidase degradation (1, 2). Previously, this Nterminal cyclization reaction was thought to proceed spontaneously, until the glutaminyl cyclases (QCs) were identified as catalysts that are responsible for this posttranslational modification (3, 4).QCs (EC 2.3.2.5) are acyltransferases that have been identified in both animal and plant sources (3-5). They are abundant in mammalian neuroendocrine tissues, such as hypothalamus and pituitary (4, 6), and are highly conserved from yeast to human. Animal QCs were shown to have distinct structure and protein stability from plant QCs despite their similar molecular masses [i.e., 33-40 kDa (5, 7)]. No bacterial QCs have been reported thus far; however, the mammalian QCs were predicted to exhibit remarkable homology to the bacterial double-zinc aminopeptidases (8, 9).In humans, several genetic diseases, such as osteoporosis, a multifactorial hormonal disease that is characterized by reduced bone mass and microarchitectural deterioration of bone tissue (10), appear to result from mutations of the QC gene. The gene encoding QC (QPCT) lies on chromosome 2p22.3. ...

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Functional Comparison of Two Human Monocyte Chemotactic Protein-2 Isoforms, Role of the Amino-Terminal Pyroglutamic Acid and Processing by CD26/Dipeptidyl Peptidase IV

Cited by 142 publications

References 48 publications

Transcriptional control of the human MCP-2 gene promoter by IFN-γ and IL-1β in connective tissue cells

Transcriptional control of the human MCP-2 gene promoter by IFN-γ and IL-1β in connective tissue cells

Truncation of Macrophage-derived Chemokine by CD26/ Dipeptidyl-Peptidase IV beyond Its Predicted Cleavage Site Affects Chemotactic Activity and CC Chemokine Receptor 4 Interaction

Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation

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