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Site specificity of DSP-PP cleavage by BMP1
Robert T Yang1, Glendale L Lim, Colin T Yee
1Department of Cariology, Restorative Sciences and Endodontics, School of Dentistry, University of Michigan , Ann Arbor, MI , USA and.
Connective Tissue Research
|August 27, 2014
Summary
Bone morphogenic protein 1 (BMP1) cleaves extracellular matrix proteins. Researchers tested mutations in dentin sialoprotein phosphophoryn (DSP-PP) and found cleavage is not based on a simple consensus sequence, suggesting conserved sites and exosites regulate efficiency.
Area of Science:
- Biochemistry
- Molecular Biology
- Extracellular Matrix Research
Background:
- Bone morphogenic protein 1 (BMP1) is a metalloproteinase involved in extracellular matrix (ECM) remodeling.
- BMP1 cleaves various ECM proteins, leading to the hypothesis of a consensus substrate cleavage sequence.
- Previous studies proposed a consensus sequence (xMQx|DDP) based on limited substrate homology, but it remained untested.
Purpose of the Study:
- To investigate whether a consensus amino acid sequence dictates Bone morphogenic protein 1 (BMP1) substrate cleavage.
- To determine the role of specific amino acid residues within and flanking the cleavage site of dentin sialoprotein phosphophoryn (DSP-PP) in its processing by BMP1.
Main Methods:
- Recombinant uncleaved dentin sialoprotein phosphophoryn (DSP-PP) was produced using an Sf9 cell expression system.
- Point mutations were introduced into DSP-PP, targeting the proposed P4-P4' cleavage site.
- Cleavage efficiencies of wild-type and mutant DSP-PP by tolloid-related protein 1 (TLR-1) and BMP1 were measured.
Main Results:
- Mutations within or outside the P4-P4' region significantly altered DSP-PP cleavage.
- Cleavage efficiency was either blocked, impaired, or accelerated by specific mutations.
- Results indicate that BMP1 cleavage is not governed by a simple consensus sequence alone.
Conclusions:
- The BMP1 cleavage site in DSP-PP is highly conserved to regulate cleavage efficiency.
- Conserved exosites may also play a role in assisting BMP1 in substrate recognition and cleavage.
- BMP1-mediated proteolysis is a complex process, not solely dependent on a universal consensus cleavage motif.
