Neurotrophins

The neurotrophins share a pairwise sequence identity of about 50% and belong to the family of cystine-knot-containing growth factors [3]. They adopt very similar three-dimensional structures, containing a monomer core of a pair of irregular, anti-parallel, two-stranded P-sheets that carry the cystine-knot motif as well as both termini on one end of the molecule and three hairpin loops on the other [4] (Fig. 1A). Two monomers are assembled in a parallel fashion to yield a non-covalent but tightly packed homodimer with a dumbbell-like shape (Fig. 1B). The conserved residues are clustered in distinct segments that cover about half of the molecule and share a local sequence identity among all neurotrophins of about 70%. Three of these segments map onto three of the P-strands that form the "handle" of the dumbbell as well as a large portion of the dimer interface. To date, crystal structures have been reported for the uncomplexed NGF, NT-3, and NT-4/5 homodimers as well as the BDNF/NT-3 and BDNF/NT-4/5 heterodimers. These structures, in combination with a wealth of mutagenesis studies and truncation experiments, have led to a good understanding of how affinity and specificity between neurotrophins and the Trk receptors are achieved, as demonstrated by the successful creation of multi- and pan-specific neurotrophin variants (reviewed in Wiesmann and de Vos[5]; also see Robinson et al. [6]).

'Current address: Department of Protein Engineering, Genentech, Inc., South San Francisco, California

Copyright © 2003, Elsevier Science (USA).

Handbook of Cell Signaling, Volume 1 281 All rights reserved.

Figure 1 The neurotrophin fold, as exemplified by NGF (taken from the NGF-TrkA-D5 complex [11]); all subsequent figures display NGF in orientations similar to that shown in part (B). One loop, bounded by residues 60 and 67, is poorly ordered or disordered in most neurotrophin structures. (A) Ribbon rendering of the backbone of the NGF monomer. The cystine knot is shown as a ball and stick. (B) Ribbon rendering of the backbone of the NGF dimer.

Figure 1 The neurotrophin fold, as exemplified by NGF (taken from the NGF-TrkA-D5 complex [11]); all subsequent figures display NGF in orientations similar to that shown in part (B). One loop, bounded by residues 60 and 67, is poorly ordered or disordered in most neurotrophin structures. (A) Ribbon rendering of the backbone of the NGF monomer. The cystine knot is shown as a ball and stick. (B) Ribbon rendering of the backbone of the NGF dimer.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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