Collagenolytic Matrix Metalloproteinase Activities toward Peptomeric Triple-Helical Substrates.

Although collagenolytic matrix metalloproteinases (MMPs) possess common domain organizations, there are subtle differences in their processing of collagenous triple-helical substrates. In this study, we have incorporated peptoid residues into collagen model triple-helical peptides and examined MMP activities toward these peptomeric chimeras. Several different peptoid residues were incorporated into triple-helical substrates at subsites P3, P1, P1', and P10' individually or in combination, and the effects of the peptoid residues were evaluated on the activities of full-length MMP-1, MMP-8, MMP-13, and MMP-14/MT1-MMP. Most peptomers showed little discrimination between MMPs. However, a peptomer containing N-methyl Gly (sarcosine) in the P1' subsite and N-isobutyl Gly (NLeu) in the P10' subsite was hydrolyzed efficiently only by MMP-13 [nomenclature relative to the α1(I)772-786 sequence]. Cleavage site analysis showed hydrolysis at the Gly-Gln bond, indicating a shifted binding of the triple helix compared to the parent sequence. Favorable hydrolysis by MMP-13 was not due to sequence specificity or instability of the substrate triple helix but rather was based on the specific interactions of the P7' peptoid residue with the MMP-13 hemopexin-like domain. A fluorescence resonance energy transfer triple-helical peptomer was constructed and found to be readily processed by MMP-13, not cleaved by MMP-1 and MMP-8, and weakly hydrolyzed by MT1-MMP. The influence of the triple-helical structure containing peptoid residues on the interaction between MMP subsites and individual substrate residues may provide additional information about the mechanism of collagenolysis, the understanding of collagen specificity, and the design of selective MMP probes.

[1]  D. Slatter,et al.  The Recognition of Collagen and Triple-helical Toolkit Peptides by MMP-13 , 2014, The Journal of Biological Chemistry.

[2]  M. Broda,et al.  Solvent effects on the conformational preferences of model peptoids. MP2 study , 2014, Journal of peptide science : an official publication of the European Peptide Society.

[3]  G. Fields,et al.  The Role of Collagen Charge Clusters in the Modulation of Matrix Metalloproteinase Activity* , 2013, The Journal of Biological Chemistry.

[4]  D. Svergun,et al.  Examination of Matrix Metalloproteinase-1 in Solution , 2013, The Journal of Biological Chemistry.

[5]  E. Stura,et al.  Crystal structure of full‐length human collagenase 3 (MMP‐13) with peptides in the active site defines exosites in the catalytic domain , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  A. Barron,et al.  A Readily Applicable Strategy to Convert Peptides to Peptoid-based Therapeutics , 2013, PloS one.

[7]  G. Fields.  Interstitial Collagen Catabolism* , 2013, The Journal of Biological Chemistry.

[8]  Jonas S. Laursen,et al.  Cis-trans amide bond rotamers in β-peptoids and peptoids: evaluation of stereoelectronic effects in backbone and side chains. , 2013, Journal of the American Chemical Society.

[9]  J. Enghild,et al.  Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1 , 2012, Proceedings of the National Academy of Sciences.

[10]  M. Inouye,et al.  Defining Requirements for Collagenase Cleavage in Collagen Type III Using a Bacterial Collagen System* , 2012, The Journal of Biological Chemistry.

[11]  I. Bertini,et al.  Structural basis for matrix metalloproteinase 1-catalyzed collagenolysis. , 2012, Journal of the American Chemical Society.

[12]  G. Fields,et al.  Exosite Interactions Impact Matrix Metalloproteinase Collagen Specificities* , 2011, The Journal of Biological Chemistry.

[13]  Ida E. Andersson,et al.  (E)-alkene and ethylene isosteres substantially alter the hydrogen-bonding network in class II MHC A(q)/glycopeptide complexes and affect T-cell recognition. , 2011, Journal of the American Chemical Society.

[14]  Ida E. Andersson,et al.  Design of Glycopeptides Used to Investigate Class II MHC Binding and T-Cell Responses Associated with Autoimmune Arthritis , 2011, PloS one.

[15]  J. Chmielewski,et al.  Cross‐linked Peptoid‐Based Dimerization Inhibitors of HIV‐1 Protease , 2010, Chembiochem : a European journal of chemical biology.

[16]  R. Saykally,et al.  Monopeptide versus monopeptoid: insights on structure and hydration of aqueous alanine and sarcosine via X-ray absorption spectroscopy. , 2010, The journal of physical chemistry. B.

[17]  G. Fields.  Synthesis and biological applications of collagen-model triple-helical peptides. , 2010, Organic & biomolecular chemistry.

[18]  Scott A. Busby,et al.  Identification of Specific Hemopexin-like Domain Residues That Facilitate Matrix Metalloproteinase Collagenolytic Activity* , 2009, The Journal of Biological Chemistry.

[19]  Ronald T Raines,et al.  Collagen structure and stability. , 2009, Annual review of biochemistry.

[20]  Robert P. Hammer,et al.  Selective Modulation of Matrix Metalloproteinase 9 (MMP-9) Functions via Exosite Inhibition* , 2008, Journal of Biological Chemistry.

[21]  D. Svergun,et al.  Evidence of reciprocal reorientation of the catalytic and hemopexin-like domains of full-length MMP-12. , 2008, Journal of the American Chemical Society.

[22]  K. Brew,et al.  Differentiation of secreted and membrane-type matrix metalloproteinase activities based on substitutions and interruptions of triple-helical sequences. , 2007, Biochemistry.

[23]  A. Rowan,et al.  Activity of matrix metalloproteinase‐9 against native collagen types I and III , 2007, The FEBS journal.

[24]  K. Brew,et al.  The Roles of Substrate Thermal Stability and P2 and P1′ Subsite Identity on Matrix Metalloproteinase Triple-helical Peptidase Activity and Collagen Specificity* , 2006, Journal of Biological Chemistry.

[25]  Federico D. Sacerdoti,et al.  Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters , 2006, ACM/IEEE SC 2006 Conference (SC'06).

[26]  C. Overall,et al.  TIMP Independence of Matrix Metalloproteinase (MMP)-2 Activation by Membrane Type 2 (MT2)-MMP Is Determined by Contributions of Both the MT2-MMP Catalytic and Hemopexin C Domains* , 2006, Journal of Biological Chemistry.

[27]  K. Acharya,et al.  Crystal Structure of an Active Form of Human MMP-1 , 2006, Journal of molecular biology.

[28]  Richard A. Friesner,et al.  Integrated Modeling Program, Applied Chemical Theory (IMPACT) , 2005, J. Comput. Chem..

[29]  Xiaoping Xu,et al.  Functional basis for the overlap in ligand interactions and substrate specificities of matrix metalloproteinases-9 and -2. , 2005, The Biochemical journal.

[30]  A. Jaśkiewicz,et al.  Examples of Peptide–Peptoid Hybrid Serine Protease Inhibitors Based on the Trypsin Inhibitor SFTI‐1 with Complete Protease Resistance at the P1P1′ Reactive Site , 2005, Chembiochem : a European journal of chemical biology.

[31]  G. Fields,et al.  Matrix metalloproteinase triple-helical peptidase activities are differentially regulated by substrate stability. , 2004, Biochemistry.

[32]  C. López-Otín,et al.  Use of a multiple-enzyme/multiple-reagent assay system to quantify activity levels in samples containing mixtures of matrix metalloproteinases. , 2004, Biochemistry.

[33]  Cathy H. Wu,et al.  Protein sequence databases. , 2004, Current opinion in chemical biology.

[34]  M. Schwartz,et al.  Catalytic- and ecto-domains of membrane type 1-matrix metalloproteinase have similar inhibition profiles but distinct endopeptidase activities. , 2004, The Biochemical journal.

[35]  M. Stack,et al.  Selective Hydrolysis of Triple-helical Substrates by Matrix Metalloproteinase-2 and -9* , 2003, The Journal of Biological Chemistry.

[36]  C. Overall.  Molecular determinants of metalloproteinase substrate specificity , 2002, Molecular biotechnology.

[37]  Jeffrey W. Smith,et al.  A Unique Substrate Binding Mode Discriminates Membrane Type-1 Matrix Metalloproteinase from Other Matrix Metalloproteinases* , 2002, The Journal of Biological Chemistry.

[38]  L. Matrisian,et al.  Matrix metalloproteinases: they're not just for matrix anymore! , 2001, Current opinion in cell biology.

[39]  L. Cantley,et al.  Determination of protease cleavage site motifs using mixture-based oriented peptide libraries , 2001, Nature Biotechnology.

[40]  M. Weiner,et al.  Substrate Specificity of Human Collagenase 3 Assessed Using a Phage-displayed Peptide Library* , 2000, The Journal of Biological Chemistry.

[41]  H. J. Griesser,et al.  Peptoid-containing collagen mimetics with cell binding activity. , 2000, Journal of biomedical materials research.

[42]  G. Fields,et al.  Use of Edman degradation sequence analysis and matrix-assisted laser desorption/ionization mass spectrometry in designing substrates for matrix metalloproteinases. , 2000, Journal of chromatography. A.

[43]  Y. Sugimoto,et al.  Identification of substrate sequences for membrane type-1 matrix metalloproteinase using bacteriophage peptide display library. , 1999, Biochemical and biophysical research communications.

[44]  G. Melacini,et al.  Collagen-based structures containing the peptoid residue N-isobutylglycine (Nleu): synthesis and biophysical studies of Gly-Pro-Nleu sequences by circular dichroism, ultraviolet absorbance, and optical rotation. , 1998, Biopolymers.

[45]  P. Basset,et al.  Membrane Type-1 Matrix Metalloprotease and Stromelysin-3 Cleave More Efficiently Synthetic Substrates Containing Unusual Amino Acids in Their P1′ Positions* , 1998, The Journal of Biological Chemistry.

[46]  G. Melacini,et al.  Collagen-based structures containing the peptoid residue N-isobutylglycine (Nleu): conformational analysis of Gly-Nleu-Pro sequences by 1H-NMR and molecular modeling. , 1997, Biochemistry.

[47]  G. Melacini,et al.  Collagen-based structures containing the peptoid residue N-isobutylglycine (Nleu): synthesis and biophysical studies of Gly-Nleu-Pro sequences by circular dichroism and optical rotation. , 1997, Biochemistry.

[48]  C. López-Otín,et al.  The Role of the C-terminal Domain of Human Collagenase-3 (MMP-13) in the Activation of Procollagenase-3, Substrate Specificity, and Tissue Inhibitor of Metalloproteinase Interaction* , 1997, The Journal of Biological Chemistry.

[49]  Y. Okada,et al.  Membrane Type 1 Matrix Metalloproteinase Digests Interstitial Collagens and Other Extracellular Matrix Macromolecules* , 1997, The Journal of Biological Chemistry.

[50]  R R Brentani,et al.  Collagen/collagenase interaction: Does the enzyme mimic the conformation of its own substrate? , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[51]  G. Fields,et al.  Promotion of Fibroblast Adhesion by Triple-helical Peptide Models of Type I Collagen-derived Sequences (*) , 1996, The Journal of Biological Chemistry.

[52]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[53]  Y. Itoh,et al.  Steps involved in activation of the complex of pro-matrix metalloproteinase 2 (progelatinase A) and tissue inhibitor of metalloproteinases (TIMP)-2 by 4-aminophenylmercuric acetate. , 1995, The Biochemical journal.

[54]  C. Overall,et al.  Extracellular matrix binding properties of recombinant fibronectin type II-like modules of human 72-kDa gelatinase/type IV collagenase. High affinity binding to native type I collagen but not native type IV collagen , 1995, The Journal of Biological Chemistry.

[55]  R. Zuckermann,et al.  Proteolytic studies of homologous peptide and N-substituted glycine peptoid oligomers , 1994 .

[56]  H M Berman,et al.  Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. , 1994, Science.

[57]  R. Jaenisch,et al.  Susceptibility of type I collagen containing mutated alpha 1(1) chains to cleavage by human neutrophil collagenase. , 1993, Matrix.

[58]  Y. DeClerck,et al.  Fragmentation of human polymorphonuclear-leucocyte collagenase. , 1993, The Biochemical journal.

[59]  J. O'Connell,et al.  The role of the C-terminal domain in collagenase and stromelysin specificity. , 1992, The Journal of biological chemistry.

[60]  R. Jaenisch,et al.  Generation of collagenase-resistant collagen by site-directed mutagenesis of murine pro alpha 1(I) collagen gene. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[61]  I. Clark,et al.  Fragments of human fibroblast collagenase. Purification and characterization. , 1989, The Biochemical journal.

[62]  A. Berger,et al.  On the size of the active site in proteases. I. Papain. , 1967, Biochemical and biophysical research communications.

[63]  M. Stawikowski.  Peptoids and peptide-peptoid hybrid biopolymers as peptidomimetics. , 2013, Methods in molecular biology.

[64]  Y. Kang,et al.  Ab initio conformational study of N-acetyl-L-proline-N', N'-dimethylamide: a model for polyproline , 2005 .

[65]  A. Sali,et al.  Modeller: generation and refinement of homology-based protein structure models. , 2003, Methods in enzymology.

[66]  R. Raines,et al.  Insights on the conformational stability of collagen. , 2002, Natural product reports.

[67]  M. Goodman,et al.  Triple helical stabilities of guest-host collagen mimetic structures. , 1999, Bioorganic & medicinal chemistry.

[68]  G. Fields,et al.  Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides. , 1996, Biopolymers.