title: A disintegrin-like and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) is a novel fibrillin-1-, fibrillin-2-, and heparin-binding member of the ADAMTS superfamily containing a netrin-like module.
abstract: ADAMTS-like proteins are related to ADAMTS metalloproteases by their similarity to ADAMTS ancillary domains. Here, we have characterized ADAMTSL5, a novel member of the superfamily with a unique modular organization that includes a single C-terminal netrin-like (NTR) module. Alternative splicing of ADAMTSL5 at its 5' end generates two transcripts that encode different signal peptides, but the same mature protein. These transcripts differ in their translational efficiency. Recombinant ADAMTSL5 is a secreted, N-glycosylated 60kDa glycoprotein located in the subcellular matrix, on the cell-surface, and in the medium of transfected cells. RT-PCR and western blot analysis of adult mouse tissues showed broad expression. Western blot analysis suggested proteolytic release of the NTR module in transfected cells as well as in some mouse tissues. Immunostaining during mouse organogenesis identified ADAMTSL5 in musculoskeletal tissues such as skeletal muscle, cartilage and bone, as well as in many epithelia. Affinity-chromatography demonstrated heparin-binding of ADAMTSL5 through its NTR-module. Recombinant ADAMTSL5 bound to both fibrillin-1 and fibrillin-2, and co-localized with fibrillin microfibrils in the extracellular matrix of cultured fibroblasts, but without discernible effect on microfibril assembly. ADAMTSL5 is the first family member shown to bind both fibrillin-1 and fibrillin-2. Like other ADAMTS proteins implicated in microfibril biology through identification of human and animal mutations, ADAMTSL5 could have a role in modulating microfibril functions.
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Bader
authors.forename: Lauren W
authors.initials: LW
authors.lastname: Wang
authors.forename: Jason C
authors.initials: JC
authors.lastname: Ho
authors.forename: Thu
authors.initials: T
authors.lastname: Tran
authors.forename: Paul
authors.initials: P
authors.lastname: Holden
authors.forename: Jamie
authors.initials: J
authors.lastname: Fitzgerald
authors.forename: Radhika P
authors.initials: RP
authors.lastname: Atit
authors.forename: Dieter P
authors.initials: DP
authors.lastname: Reinhardt
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071096:ADAMTS Proteins; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D020894:Microfibrils / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D000075388:Netrin-1; D011994:Recombinant Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D054392:Adipokines
chemical_list: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D006493:Heparin; D008840:Microfilament Proteins; D009414:Nerve Growth Factors; D000075388:Netrin-1; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D025521:Tumor Suppressor Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C000605724:Fbn1 protein, mouse; C000605728:Fbn2 protein, mouse; C581035:ADAMTSL5 protein, human