Insulin-like growth factor binding protein 2: NMR analysis and structural characterization of the N-terminal domain

Galea, Charles A., Mobli, Mehdi, McNeil, Kerrie A., Mulhern, Terrence D., Wallace, John C., King, Glenn F., Forbes, Briony E. and Norton, Raymond S. (2012) Insulin-like growth factor binding protein 2: NMR analysis and structural characterization of the N-terminal domain. Biochimie, 94 3: 608-616. doi:10.1016/j.biochi.2011.09.012


Author Galea, Charles A.
Mobli, Mehdi
McNeil, Kerrie A.
Mulhern, Terrence D.
Wallace, John C.
King, Glenn F.
Forbes, Briony E.
Norton, Raymond S.
Title Insulin-like growth factor binding protein 2: NMR analysis and structural characterization of the N-terminal domain
Journal name Biochimie   Check publisher's open access policy
ISSN 0300-9084
1638-6183
Publication date 2012-03
Year available 2011
Sub-type Article (original research)
DOI 10.1016/j.biochi.2011.09.012
Volume 94
Issue 3
Start page 608
End page 616
Total pages 9
Place of publication Cedex, France
Publisher Elsevier Masson
Collection year 2012
Language eng
Formatted abstract
The insulin-like growth factor binding proteins are a family of six proteins (IGFBP-1 to 6) that bind
insulin-like growth factors-I and -II (IGF-I/II) with high affinity. In addition to regulating IGF actions,
IGFBPs have IGF-independent functions. IGFBP-2, the largest member of this family, is over-expressed in
many cancers and has been proposed as a possible target for the development of novel anti-cancer
therapeutics. The IGFBPs have a common architecture consisting of conserved N- and C-terminal
domains joined by a variable linker domain. The solution structure and dynamics of the C-terminal
domain of human IGFBP-2 have been reported (Kuang Z. et al. Biochemistry, 46, 13,720e13,732, 2007)
but neither the N-domain (N-BP-2) nor the linker domain have been characterised. Here we present NMR
resonance assignments for human N-BP-2, achieved by recording spectra at low protein concentration
using non-uniform sampling and maximum entropy reconstruction. Analysis of secondary chemical
shifts shows that N-BP-2 possesses a secondary structure similar to that of other IGFBPs. Although
aggregation hampered determination of the solution structure for N-BP-2, a homology model was
generated based on the high degree of sequence and structure homology exhibited by the IGFBPs. This
model was consistent with experimental NMR and SAXS data and displayed some unique features such
as a Pro/Ala-rich non-polar insert, which formed a flexible solvent-exposed loop on the surface of the
protein opposite to the IGF-binding interface. NMR data indicated that this loop could adopt either of two
alternate conformations in solution e an entirely flexible conformation and one containing nascent
helical structure. This loop and an adjacent poly-proline sequence may comprise a potential SH3 domain
interaction site for binding to other proteins.
Keyword Insulin-like growth factor binding protein
IGFBP-2
N-Domain
NMR
Structure
SAXS
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 22 September 2011

 
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Created: Fri, 07 Oct 2011, 14:11:23 EST by Professor Glenn King on behalf of School of Chemistry & Molecular Biosciences