The tyrosine sulfate-rich domains of the LRR proteins fibromodulin and osteoadherin bind motifs of basic clusters in a variety of heparin-binding proteins, including bioactive factors.
The small leucine-rich repeat proteins, fibromodulin and osteoadherin, have N-terminal extensions with a variable number of O-sulfated tyrosine residues. This modification combined with a number of aspartic and glutamic acid residues results in a highly negatively charged domain of less than 30 amino acids. We hypothesized that this domain shares functional properties with heparin regarding binding to proteins and polypeptides containing clusters of basic amino acids. Two other family members, PRELP and chondroadherin, have distinctly different clusters of basic amino acids in their N and C termini, respectively, and PRELP is known to bind to heparin via this domain. Another heparin-binding protein is the cytokine Oncostatin M, with a different cluster of basic amino acids in its C terminus. We used polypeptides representing these basic domains in solid phase assays and demonstrate interactions with the negatively charged N-terminal domain of fibromodulin and full-length osteoadherin. The tyrosine sulfate domains also bound heparin-binding proteins such as basic fibroblast growth factor-2, thrombospondin I, MMP13, the NC4 domain of collagen IX, and interleukin-10. Fibronectin with large heparin-binding domains did not bind, neither did CILP containing a heparin-binding thrombospondin type I motif without clustered basic amino acids. Affinity depends on the number and position of the sulfated tyrosine residues shown by different binding properties of 10-kDa fragments subfractionated by ion-exchange chromatography. These interactions may sequester growth factors, cytokines, and matrix metalloproteinases in the extracellular matrix as well as contribute to its organization.
Tillgren
Viveka
V
Department of Clinical Sciences, Lund, Section for Rheumatology, Molecular Skeletal Biology, Lund University, Biomedical Center Plan C12, Lund SE-221 84, Sweden.
Onnerfjord
Patrik
P
Haglund
Lisbet
L
Heinegård
Dick
D
D020816:Amino Acid Motifs; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D001798:Blood Proteins / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D002417:Cattle; D003094:Collagen / Q000737:chemistry; D016326:Extracellular Matrix Proteins / Q000737:chemistry*; D000071235:Fibromodulin; D006801:Humans; D053683:Oncostatin M / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry*; D013431:Sulfates / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry*
C062991:AZU1 protein, human; D000596:Amino Acids; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D010455:Peptides; D011509:Proteoglycans; D013431:Sulfates; C113360:osteoadherin; D053683:Oncostatin M; D000071235:Fibromodulin; D014443:Tyrosine; D003094:Collagen
J Biol Chem. 1989 Apr 25;264(12):6898-905
2496122
J Cell Biol. 1988 Mar;106(3):991-7
3346333
Nature. 1970 Aug 15;227(5259):680-5
5432063
J Biol Chem. 2001 Jun 1;276(22):18947-52
11259413
J Biol Chem. 2000 Dec 29;275(52):40695-702
11007795
J Biol Chem. 1993 Dec 25;268(36):27307-12
8262971
J Biol Chem. 1984 Aug 25;259(16):10100-5
6236212
J Mol Biol. 1996 Dec 6;264(3):556-66
8969305
J Biol Chem. 2004 Feb 20;279(8):6286-95
14660626
J Biol Chem. 1986 Oct 15;261(29):13866-72
3759994
J Biol Chem. 2007 Jun 1;282(22):16062-7
17426031
J Biol Chem. 2001 Mar 2;276(9):6485-98
11067851
Proc Natl Acad Sci U S A. 1980 Aug;77(8):4494-8
6449008
J Biol Chem. 2004 Jan 2;279(1):26-33
14551184
J Biol Chem. 2001 Apr 13;276(15):12201-11
11152692
J Biol Chem. 2004 Jun 4;279(23):24265-73
15047691
J Biol Chem. 2001 Mar 9;276(10):7507-17
11106655
J Biol Chem. 2007 Sep 14;282(37):26740-26745
17623650
J Biol Chem. 1992 Jan 5;267(1):347-52
1370446
J Biol Chem. 1995 Feb 17;270(7):3392-9
7852425
Biochem J. 1984 Nov 1;223(3):587-97
6439184
Arthritis Rheum. 1998 Dec;41(12):2143-51
9870871
Matrix Biol. 2001 Feb;20(1):63-73
11246004
J Biol Chem. 1998 Sep 4;273(36):23463-8
9722583
J Biol Chem. 2002 Apr 26;277(17):15061-8
11847210
Biochem J. 1981 Jul 1;197(1):213-6
7317031
J Biol Chem. 1985 Sep 15;260(20):11046-52
3161889
Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3040-4
1557410
Matrix Biol. 1994 Apr;14(3):227-32
7921539
Anal Biochem. 1993 Apr;210(1):179-87
8489015
J Biol Chem. 2001 Aug 31;276(35):32883-8
11445564
J Biol Chem. 1998 Sep 4;273(36):23469-75
9722584
J Biol Chem. 1995 Sep 1;270(35):20712-6
7657652