2lkn
Solution structure of the PPIase domain of human aryl-hydrocarbon receptor-interacting protein (AIP)
Structural highlights
DiseaseAIP_HUMAN Acromegaly;Familial prolactinoma. Defects in AIP are a cause of growth hormone-secreting pituitary adenoma (GHSPA) [MIM:102200; also known as familial isolated somatotropinomas (FIS) or isolated familial somatotropinoma (IFS) or familial somatotrophinoma or acromegaly due to pituitary adenoma.[1] [2] [3] [4] Defects in AIP are a cause of ACTH-secreting pituitary adenoma (ASPA) [MIM:219090; also known as pituitary Cushing disease. A pituary adenoma resulting in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and trunkal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. Defects in AIP are a cause of prolactin-secreting pituitary adenoma (PSPA) [MIM:600634; also known as prolactinoma. Prolactin-secreting pituitary adenoma is the most common type of hormonally active pituitary adenoma. FunctionAIP_HUMAN May play a positive role in AHR-mediated (aromatic hydrocarbon receptor) signaling, possibly by influencing its receptivity for ligand and/or its nuclear targeting. Cellular negative regulator of the hepatitis B virus (HBV) X protein. Publication Abstract from PubMedThe aryl hydrocarbon receptor-interacting protein (AIP) has been predicted to consist of an N-terminal FKBP-type peptidyl-prolyl cis/trans isomerase (PPIase) domain and a C-terminal tetratricopeptide repeat (TPR) domain, as typically found in FK506-binding immunophilins. AIP, however, exhibited no inherent FK506 binding or PPIase activity. Alignment with the prototypic FKBP12 showed a high sequence homology but indicated inconsistencies with regard to the secondary structure prediction derived from chemical shift analysis of AIP2-166. NMR-based structure determination of AIP2-166 now revealed a typical FKBP fold with five antiparallel beta-strands forming a half beta-barrel wrapped around a central alpha-helix, thus permitting AIP to be also named FKBP37.7 according to FKBP nomenclature. This PPIase domain, however, features two structure elements that are unusual for FKBPs: (i) an N-terminal alpha-helix, which additionally stabilizes the domain, and (ii) a rather long insert, which connects the last two beta-strands and covers the putative active site. Diminution of the latter insert did not generate PPIase activity or FK506 binding capability, indicating that the lack of catalytic activity in AIP is the result of structural differences within the PPIase domain. Compared to active FKBPs, a diverging conformation of the loop connecting beta-strand C' and the central alpha-helix apparently is responsible for this inherent lack of catalytic activity in AIP. Moreover, Hsp90 was identified as potential physiological interaction partner of AIP, which revealed binding contacts not only at the TPR domain but uncommonly also at the PPIase domain. The FKBP-Type Domain of the Human Aryl Hydrocarbon Receptor-Interacting Protein Reveals an Unusual Hsp90 Interaction.,Linnert M, Lin YJ, Manns A, Haupt K, Paschke AK, Fischer G, Weiwad M, Lucke C Biochemistry. 2013 Mar 13. PMID:23418784[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
