Morohashi Yuichi, Hatano Noriyuki, Ohya Susumu, Takikawa Rie, Watabiki Tomonari, Takasugi Nobumasa, Imaizumi Yuji, Tomita Taisuke, Iwatsubo Takeshi
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
J Biol Chem. 2002 Apr 26;277(17):14965-75. doi: 10.1074/jbc.M200897200. Epub 2002 Feb 14.
Presenilin (PS) genes linked to early-onset familial Alzheimer's disease encode polytopic membrane proteins that are presumed to constitute the catalytic subunit of gamma-secretase, forming a high molecular weight complex with other proteins. During our attempts to identify binding partners of PS2, we cloned CALP (calsenilin-like protein)/KChIP4, a novel member of calsenilin/KChIP protein family that interacts with the C-terminal region of PS. Upon co-expression in cultured cells, CALP was directly bound to and co-localized with PS2 in endoplasmic reticulum. Overexpression of CALP did not affect the metabolism or stability of PS complex, and gamma-cleavage of betaAPP or Notch site 3 cleavage was not altered. However, co-expression of CALP and a voltage-gated potassium channel subunit Kv4.2 reconstituted the features of A-type K(+) currents and CALP directly bound Kv4.2, indicating that CALP functions as KChIPs that are known as components of native Kv4 channel complex. Taken together, CALP/KChIP4 is a novel EF-hand protein interacting with PS as well as with Kv4 that may modulate functions of a subset of membrane proteins in brain.
与早发性家族性阿尔茨海默病相关的早老素（PS）基因编码多结构域膜蛋白，这些蛋白被认为构成γ-分泌酶的催化亚基，与其他蛋白形成高分子量复合物。在我们试图鉴定PS2的结合伴侣的过程中，我们克隆了CALP（钙调神经磷酸酶样蛋白）/KChIP4，它是钙调神经磷酸酶/KChIP蛋白家族的一个新成员，可与PS的C末端区域相互作用。在培养细胞中共表达时，CALP在内质网中直接与PS2结合并共定位。CALP的过表达不影响PS复合物的代谢或稳定性，β淀粉样前体蛋白（βAPP）的γ切割或Notch位点3的切割也未改变。然而，CALP与电压门控钾通道亚基Kv4.2的共表达重建了A型钾电流的特征，并且CALP直接与Kv4.2结合，表明CALP发挥着KChIPs的功能，而KChIPs是天然Kv4通道复合物的已知组成部分。综上所述，CALP/KChIP4是一种新型的EF手蛋白，它与PS以及Kv4相互作用，可能调节大脑中一部分膜蛋白的功能。
