Collagen binding specificity of the discoidin domain receptors: Binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1

Xu, Haisheng; Raynal, Nicolas; Stathopoulos, Stavros; Myllyharju, Johanna; Farndale, Richard W.; Leitinger, Birgit

doi:10.1016/j.matbio.2010.10.004

Cited by 168 publications

(185 citation statements)

References 38 publications

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“…Detailed investigations have established relative specificity with respect to DDR-binding to alternate, non-fibrillar collagens such as the collagens IV and X and have also revealed that such specificity is defined by nonconserved residues located at the periphery of the binding trench [26]. Such investigations provide a framework by which to elaborate the detailed collagen-binding properties of CPX-1, CPX-2 and ACLP.…”

Section: Accepted Manuscriptmentioning

confidence: 92%

Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein

Kim

O’Neill

Whitehead

2015

Biochemical and Biophysical Research Communications

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Carboxypeptidase X-1 (CPX-1) is an atypical member of the carboxypeptidase (CP) family of proteins involved in a variety of physiological and pathological processes. However, unlike most other family members CPX-1 lacks catalytic activity making its biological function unclear. CPX-1 contains a 160 amino acid discoidin domain (DSD) that serves as a binding domain in other proteins prompting us to investigate a putative functional role for this domain in CPX-1.Sequence alignment confirmed the overarching homology between the DSD of CPX-1 and other DSDs whilst more detailed analysis revealed conservation of the residues known to form the collagen-binding trench within the DSD of the discoidin domain receptors (DDRs) 1 and 2.Biochemical characterisation of transiently expressed human CPX-1 revealed that CPX-1 was secreted in an N-glycosylation-dependent manner as treatment with the N-glycosylation inhibitor tunicamycin inhibited secretion concomitant with a reduction in CPX-1 mobility on Western blot. Using a collagen pull-down assay we found that secreted CPX-1 bound collagen and this appeared independent of N-glycosylation as treatment with PNGaseF did not affect binding. Further analysis under non-reducing and reducing (+DTT) conditions revealed that CPX-1 was secreted in both monomeric and dimeric forms and only the former bound collagen.Finally, mutation of a key residue situated within the putative collagen-binding trench within the DSD of CPX-1 (R192A) significantly reduced secretion and collagen-binding by 40% and 60%, respectively. Collectively these results demonstrate that CPX-1 is a secreted collagen-binding glycoprotein and provide a foundation for future studies investigating the function of CPX-1.

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Section: Accepted Manuscriptmentioning

confidence: 92%

Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein

Kim

O’Neill

Whitehead

2015

Biochemical and Biophysical Research Communications

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“…Collagen types I and III are the predominant isoforms found in the lungs (27,28), though types IV and V are also expressed (29) and are critical for lung homeostasis. Intact type IV and V collagens interact with integrins (30), matricellular proteins (31), and discoidin receptor (32) in normal physiology.…”

Section: Evolution and Remodeling Of The Ecmmentioning

confidence: 99%

Bioactive extracellular matrix fragments in lung health and disease

Gaggar¹,

Weathington²

2016

Journal of Clinical Investigation

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“…The VWF-binding site on collagen III was located to residues 572-580 of the collagen III α1 chain (8). The core VWF-binding sequence, RGQOGVMGF, is 100% conserved in collagens II and III and this motif also forms a binding site for the matrix protein SPARC (also known as osteonectin) (9) and discoidin domain receptors 1 and 2 (DDR1 and DDR2) (10,11). Interestingly, although collagen I is a good ligand for VWF, the VWF-binding sequence is only partially conserved in collagen I. Collagen I, unlike collagen III, is a heterotrimeric collagen consisting of two α1(I) chains and one α2(I) chain, where the collagen chain register, i.e., the relative position of the α2 chain in the heterotrimer, is unknown.…”

mentioning

confidence: 99%

Implications for collagen I chain registry from the structure of the collagen von Willebrand factor A3 domain complex

Brondijk

Bihan²,

Farndale³

et al. 2012

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

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Fibrillar collagens, the most abundant proteins in the vertebrate body, are involved in a plethora of biological interactions. Plasma protein von Willebrand factor (VWF) mediates adhesion of blood platelets to fibrillar collagen types I, II, and III, which is essential for normal haemostasis. High affinity VWF-binding sequences have been identified in the homotrimeric collagen types II and III, however, it is unclear how VWF recognizes the heterotrimeric collagen type I, the superstructure of which is unknown. Here we present the crystal structure of VWF domain A3 bound to a collagen type III-derived homotrimeric peptide. Our structure reveals that VWF-A3 interacts with all three collagen chains and binds through conformational selection to a sequence that is one triplet longer than was previously appreciated from platelet and VWF binding studies. The VWF-binding site overlaps those of SPARC (also known as osteonectin) and discodin domain receptor 2, but is more extended and shifted toward the collagen amino terminus. The observed collagen-binding mode of VWF-A3 provides direct structural constraints on collagen I chain registry. A VWF-binding site can be generated from the sequences RGQAGVMF, present in the two α1 (I) chains, and RGEOGNIGF, in the unique α2(I) chain, provided that α2(I) is in the middle or trailing position. Combining these data with previous structural data on integrin binding to collagen yields strong support for the trailing position of the α2(I) chain, shedding light on the fundamental and long-standing question of the collagen I chain registry.X-ray crystallography | extracellular matrix V on Willebrand factor (VWF) mediates blood platelet adhesion to sites of vascular damage and is essential for platelet adhesion under conditions of high shear stress. Defective processing and/or mutations in VWF are associated with various haemostatic disorders such as haemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and von Willebrand disease, which is the most common genetic bleeding disorder in humans (1). The mature VWF protein consists of 2,050 amino acid monomers that are disulfide-linked into multimers ranging from 0.5 to 10 MDa in size with the larger multimers being more active in hemostasis. VWF multimer size is regulated by ADAMTS13 through proteolytic cleavage within the VWF A2 domain. Upon vascular damage, the VWF A3 domain interacts with exposed collagens I and III. Subsequent transient interactions between the VWF A1 domain and Glycoprotein Ibα (GPIbα) on the surface of blood platelets reduces platelet velocity to allow subsequent stable platelet adhesion and activation, which ultimately results in thrombus deposition.The crystal structure of the collagen-binding VWF A3 domain has been solved (2-4) and the collagen-binding site within the A3 domain has been mapped in extensive site-directed mutagenesis studies and by NMR (5-7). However, detailed structural information on the VWF-collagen interaction has thus far been lacking.Collagens, the most abundant proteins in mammalian...

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Collagen binding specificity of the discoidin domain receptors: Binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1

Cited by 168 publications

References 38 publications

Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein

Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein

Bioactive extracellular matrix fragments in lung health and disease

Implications for collagen I chain registry from the structure of the collagen von Willebrand factor A3 domain complex

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