Abstract
The homodimerization of ENPP1 is mediated by the two somatomedin B (SMB) domains of the protein through a mechanism that is yet unknown at the atomistic level. The tandem arrangement of these domains without an intermediate spacer implies their possible packing into a functional assembly, which we explored by rigid docking. To exclude potential bias in the docking search we assessed the absence of flexible protein regions by evaluating the normalized B-factors calculated from the Cα atom displacements derived from molecular dynamics simulations. After filtering the docking results exploiting the criterion that residues located at the inter-domain interfaces are more conserved than non-interface residues, the resulting best model of the tandem SMB domains revealed the presence of two large conserved surface patches not engaged in the inter-domain contact. The largest patch is flat and contains all the invariant positively charged residues characterized by fully solvent-exposed side chains within the tandem SMB domains, suggesting as a possible role its interaction with the negative phospholipids on the cell surface. We envisage that an ENPP1 monomer bound to the cell membrane via the transmembrane segment can also interact with the cell surface through the largest conserved patch favoring a specific geometry of the tandem SMB module on the cell that optimally exposes the second conserved patch for the symmetric interaction with another membrane-bound ENPP1 monomer, finally promoting the homodimerization. Biological implications of this model and insights into the effects of the K173Q variant associated with insulin resistance and related abnormalities are presented.
| Original language | English |
|---|---|
| Pages (from-to) | 3566-3574 |
| Number of pages | 9 |
| Journal | Journal of Cellular Physiology |
| Volume | 227 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2012 |
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ASJC Scopus subject areas
- Clinical Biochemistry
- Cell Biology
- Physiology
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In silico analysis of the two tandem somatomedin B domains of ENPP1 reveals hints on the homodimerization of the protein. / Bellacchio, Emanuele.
In: Journal of Cellular Physiology, Vol. 227, No. 11, 11.2012, p. 3566-3574.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In silico analysis of the two tandem somatomedin B domains of ENPP1 reveals hints on the homodimerization of the protein
AU - Bellacchio, Emanuele
PY - 2012/11
Y1 - 2012/11
N2 - The homodimerization of ENPP1 is mediated by the two somatomedin B (SMB) domains of the protein through a mechanism that is yet unknown at the atomistic level. The tandem arrangement of these domains without an intermediate spacer implies their possible packing into a functional assembly, which we explored by rigid docking. To exclude potential bias in the docking search we assessed the absence of flexible protein regions by evaluating the normalized B-factors calculated from the Cα atom displacements derived from molecular dynamics simulations. After filtering the docking results exploiting the criterion that residues located at the inter-domain interfaces are more conserved than non-interface residues, the resulting best model of the tandem SMB domains revealed the presence of two large conserved surface patches not engaged in the inter-domain contact. The largest patch is flat and contains all the invariant positively charged residues characterized by fully solvent-exposed side chains within the tandem SMB domains, suggesting as a possible role its interaction with the negative phospholipids on the cell surface. We envisage that an ENPP1 monomer bound to the cell membrane via the transmembrane segment can also interact with the cell surface through the largest conserved patch favoring a specific geometry of the tandem SMB module on the cell that optimally exposes the second conserved patch for the symmetric interaction with another membrane-bound ENPP1 monomer, finally promoting the homodimerization. Biological implications of this model and insights into the effects of the K173Q variant associated with insulin resistance and related abnormalities are presented.
AB - The homodimerization of ENPP1 is mediated by the two somatomedin B (SMB) domains of the protein through a mechanism that is yet unknown at the atomistic level. The tandem arrangement of these domains without an intermediate spacer implies their possible packing into a functional assembly, which we explored by rigid docking. To exclude potential bias in the docking search we assessed the absence of flexible protein regions by evaluating the normalized B-factors calculated from the Cα atom displacements derived from molecular dynamics simulations. After filtering the docking results exploiting the criterion that residues located at the inter-domain interfaces are more conserved than non-interface residues, the resulting best model of the tandem SMB domains revealed the presence of two large conserved surface patches not engaged in the inter-domain contact. The largest patch is flat and contains all the invariant positively charged residues characterized by fully solvent-exposed side chains within the tandem SMB domains, suggesting as a possible role its interaction with the negative phospholipids on the cell surface. We envisage that an ENPP1 monomer bound to the cell membrane via the transmembrane segment can also interact with the cell surface through the largest conserved patch favoring a specific geometry of the tandem SMB module on the cell that optimally exposes the second conserved patch for the symmetric interaction with another membrane-bound ENPP1 monomer, finally promoting the homodimerization. Biological implications of this model and insights into the effects of the K173Q variant associated with insulin resistance and related abnormalities are presented.
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UR - http://www.scopus.com/inward/citedby.url?scp=84864095449&partnerID=8YFLogxK
U2 - 10.1002/jcp.24058
DO - 10.1002/jcp.24058
M3 - Article
C2 - 22262087
AN - SCOPUS:84864095449
VL - 227
SP - 3566
EP - 3574
JO - Journal of cellular and comparative physiology
JF - Journal of cellular and comparative physiology
SN - 0021-9541
IS - 11
ER -