title: Biophysical studies with AICD-47 reveal unique binding behavior characteristic of an unfolded domain.
abstract: APP intracellular C-terminal domain (AICD-47), generated upon γ-secretase cleavage of amyloid precursor's protein (APP), bears the signature of a classical intrinsically unstructured domain (IUD). Comparing the recent crystal structures of AICD-47 peptides bound to its different adaptors such as protein-tyrosine-binding domain-2 (PTB2) of Fe65 and Src homology 2 (SH2) domain of growth factor receptor binding protein 2 (Grb2), the "conformational switching" of AICD-47 becomes evident. In order to understand different binding processes undertaken by this flexible molecule, upon recognizing different interfaces resulting in different 3D conformations, spectroscopic and calorimetric studies have been done. CD spectroscopy has revealed an overall random coil like structure in different pHs while TFE (2'-2'-2'-trifluoro ethanol) and HFIP (Hexa fluoro isopropanol) induced α-helicity to a certain extent. Binding of Tyr phosphorylated AICD-47 ((P)AICD-47) to Grb2-SH2 domain was carried out by a favorable enthalpic change (ΔH=-197.5±6.2 kcal mole(-1) at 25 °C) and an unfavorable entropic contribution (ΔS=-631 cal mol(-1) deg(-1) at 25 °C). Alternative conformation of AICD-47 in different biological contexts is another remarkable feature of IUDs which presumably has definitive roles in regulating Alzheimer's disease phenotype.
authors: Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700 064, WB, India.
authors: Samir
authors: S
authors: Das
authors: Saptaparni
authors: S
authors: Ghosh
authors: Dipak
authors: D
authors: Dasgupta
authors: Udayaditya
authors: U
authors: Sen
authors: Debashis
authors: D
authors: Mukhopadhyay
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D011992:Endosomes / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000737:chemistry; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D021381:Protein Transport; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains
chemical_list: D016564:Amyloid beta-Protein Precursor; D051380:GRB2 Adaptor Protein; D010446:Peptide Fragments; D014443:Tyrosine