Journal Article

PUBDB-2016-00526

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Conundrum of the High-Affinity NGF Binding Site Formation Unveiled?

Covaceuszach, S.>Extern* ; Konarev, P.EMBL* ; Cassetta, A. ; Paoletti, F.>Extern* ; Svergun, D.EMBL* ; Lamba, D. (Corresponding author) ; Cattaneo, A. (Corresponding author)

2015
Cell Press Cambridge, Mass.

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Please use a persistent id in citations: doi:10.1016/j.bpj.2014.11.3485

Abstract: The homodimer NGF (nerve growth factor) exerts its neuronal activity upon binding to either or both distinct transmembrane receptors TrkA and $p75^{NTR}$. Functionally relevant interactions between NGF and these receptors have been proposed, on the basis of binding and signaling experiments. Namely, a ternary $TrkA/NGF/p75^{NTR}$ complex is assumed to be crucial for the formation of the so-called high-affinity NGF binding sites. However, the existence, on the cell surface, of direct extracellular interactions is still a matter of controversy. Here, supported by a small-angle x-ray scattering solution study of human NGF, we propose that it is the oligomerization state of the secreted NGF that may drive the formation of the ternary heterocomplex. Our data demonstrate the occurrence in solution of a concentration-dependent distribution of dimers and dimer of dimers. A head-to-head molecular assembly configuration of the NGF dimer of dimers has been validated. Overall, these findings prompted us to suggest a new, to our knowledge, model for the transient ternary heterocomplex, i.e., a $TrkA/NGF/p75^{NTR}$ ligand/receptors molecular assembly with a (2:4:2) stoichiometry. This model would neatly solve the problem posed by the unconventional orientation of $p75^{NTR}$ with respect to TrkA, as being found in the crystal structures of the TrkA/NGF and $p75^{NTR}/NGF$ complexes.

Note: (c) by the Biophysical Society

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Contributing Institute(s):

1. EMBL (EMBL)
2. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (POF3-622) (POF3-622)

Experiment(s):

1. DORIS Beamline D1.2 (DORIS III)
2. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2015

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Database coverage:
; ; BIOSIS Previews ; Current Contents - Life Sciences ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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