Role of variable beta-hairpin loop in determining biological specificities in neurotrophin family.
نویسندگان
چکیده
The neurotrophins are members of a family of structurally and functionally related neurotrophic factors that control the development and maintenance of vertebrate neurons. The crystal structure of nerve growth factor (NGF), the prototypic member of this family, contains three pairs of anti-parallel beta-strands connected by beta-hairpin loops, which contain most of the variable residues among the four neurotrophin proteins. Recently, amino acid residues in these variable loop regions have been implicated in the interaction between NGF and its signal-transducing receptor TrkA. In NGF, residues 40-49 (variable region II) span a very flexible and solvent-accessible beta-hairpin loop that is highly variable between different neurotrophins. To investigate the role of this domain in determining biological specificities in the neurotrophin family, we constructed a series of chimeric molecules by exchanging this variable region among three neurotrophins (i.e. NGF, neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)) that bind and activate three different Trk receptors (i.e. TrkA, -C, and -B, respectively). The chimeric molecules were analyzed for their ability to activate different Trk receptor subtypes and to promote the survival of subpopulations of peripheral neurons expressing specific types of Trk mRNAs. Exchange of the 40-49 variable loop region between NGF and NT-3 resulted in molecules capable of activating both TrkA and TrkC receptors and of rescuing neurons containing TrkA and TrkC mRNAs, indicating that this loop plays an important role in determining biological specificities in these two neurotrophins. Furthermore, variable region II from NT-4 conferred the ability to differentiate nnr5 PC12-TrkB cells to a chimeric NT-3 molecule that was originally incapable of eliciting a response in these cells. In contrast, exchanges between NGF and NT-4 did not suffice to generate molecules with broader biological specificities, suggesting that other regions in these molecules are also required. Our results support the evolutionary relationships between the three polypeptides deduced from structural comparisons.
منابع مشابه
Functional analysis of mutant neurotrophins deficient in low-affinity binding reveals a role for p75LNGFR in NT-4 signalling.
The neurotrophins mediate their effects through binding to two classes of receptors, a tyrosine kinase receptor, member of the Trk family, and the low-affinity neurotrophin receptor, p75LNGFR, of as yet undefined signalling capacity. The need for a two-component receptor system in neurotrophin signalling is still not understood. Using site-directed mutagenesis, we have identified positively cha...
متن کاملNucleotide and translated amino acid sequences of cDNA coding for the variable regions of the light and heavy chains of mouse hybridoma antibodies to blood group A and B substances.
This is the first report of nucleotide and translated amino acid sequences of the variable region light (VL) and heavy (VH) chains of mouse monoclonal hybridoma anti-blood group A and B substances, the combining sites of which have been mapped. Monoclonal hybridoma anti-A and anti-B produced in BALB/c mice by immunization with A or B blood group substances, with A1 erythrocytes, and water-solub...
متن کاملAn extended surface of binding to Trk tyrosine kinase receptors in NGF and BDNF allows the engineering of a multifunctional pan-neurotrophin.
Neurotrophin-mediated cell survival and differentiation of vertebrate neurons is caused by ligand-specific binding to the Trk family of tyrosine kinase receptors. However, sites in the neurotrophins responsible for the binding to Trk receptors and the mechanisms whereby this interaction results in receptor activation and biological activity are unknown. Here we show that in nerve growth factor ...
متن کاملRole of Work-Family Facilitation on Family Satisfaction and Life Satisfaction among Female Nurses: Structural Equation Modeling
Background and Objectives: Exchanging experiences and opportunities of work place with family and vice versa can be fundamental to lives of female nurses. This study was conducted to investigate the role of work-family facilitation on family satisfaction and life satisfaction among female nurses. Materials and Methods: In this correlational study, 221 female nurses working in two public hosp...
متن کاملThe Bowman-Birk inhibitor reactive site loop sequence represents an independent structural beta-hairpin motif.
We have determined the NMR structure in aqueous solution of a disulphide-cyclised 11-residue peptide that forms a stable beta-hairpin, incorporating a type VIb beta-turn. The structure is found to be extremely well ordered for a short peptide, with the 30 lowest energy simulated annealing structures having an average pairwise r.m.s. deviation of only 0.36 A over the backbone. All but three side...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- The Journal of biological chemistry
دوره 269 31 شماره
صفحات -
تاریخ انتشار 1994