Calnexin, More Than Just a Molecular Chaperone

Abstract

Calnexin is a type I integral endoplasmic reticulum (ER) membrane protein with an N-terminal domain that resides in the lumen of the ER and a C-terminal domain that extends into the cytosol. Calnexin is commonly referred to as a molecular chaperone involved in the folding and quality control of membrane-associated and secreted proteins, a function that is attributed to its ER- localized domain with a structure that bears a strong resemblance to another luminal ER chaperone and Ca2+-binding protein known as calreticulin. Studies have discovered that the cytosolic C-terminal domain of calnexin undergoes distinct post-translational modifications and interacts with a variety of proteins. Here, we discuss recent findings and hypothesize that the post-translational modifications of the calnexin C-terminal domain and its interaction with specific cytosolic proteins play a role in coordinating ER functions with events taking place in the cytosol and other cellular compartments.

Importance of fatty acid binding proteins in cellular function and organismal metabolism

“… 95 Calnexin is an endoplasmic reticulum‐resident protein chaperone that is structurally related to another endoplasmic reticulum‐resident calcium binding protein known as calreticulin. 98 However, unlike calreticulin which is a luminal endoplasmic reticulum protein, calnexin is comprised of an N‐terminal domain that is situated in the lumen of the endoplasmic reticulum, a transmembrane domain and a C‐terminal region that is exposed to the cytosol. Importantly, Fabp5 is capable of forming stable interactions with the cytosolic C‐tail domain of calnexin.…”

Calreticulin: Endoplasmic reticulum Ca2+ gatekeeper

“…In contrast calnexin movement is restricted in the ER because it is an integral ER membrane protein anchored to the membrane via a transmembrane helix followed by large cytoplasmic domain (Figure 5). 59 The chaperone function of calreticulin and calnexin ER luminal domain is interchangeable but the spectrum of glycoproteins that calreticulin or calnexin bind is determined by topological environment, that is whether they are attached to a membrane (calnexin) or are free in the ER lumen (calreticulin) 182 . Regardless, both proteins require the presence of Ca 2+ (supplied by calreticulin) to perform their role of chaperones 60,66 …”

“…One important advance in our understanding of the structure of calreticulin was the elucidation of the crystal structure of the luminal domain of calnexin. Calnexin shares similarity with calreticulin's amino acid sequence encoding N‐ and P‐domains 59,73,97,98 . Combined with solving the structure of the P‐domain of calreticulin by NMR technique, 64 the 3D structure provided for the first‐time structural information on calreticulin (reviewed in 38 ).…”

“…Except for their unique C‐terminal domains, calreticulin and calnexin, a type 1 integral ER membrane chaperone (discussed below), share many structural features. 17 , 59 However, the human calnexin gene ( CANX ) consist of 15 exons (33 kb) encoding 592 amino acid residue polypeptide and it is located on chromosome 5. 59 , 60 Furthermore, phylogenetic analysis indicates that calreticulin and calnexin existed as separate proteins derived from independent clades.…”

“… 17 , 59 However, the human calnexin gene ( CANX ) consist of 15 exons (33 kb) encoding 592 amino acid residue polypeptide and it is located on chromosome 5. 59 , 60 Furthermore, phylogenetic analysis indicates that calreticulin and calnexin existed as separate proteins derived from independent clades. 61 It is important to realize that calnexin is anchored to the ER membrane by transmembrane domain with limited mobility in the ER 59 whereas calreticulin is a resident ER luminal protein with high Ca 2+ binding capacity free to move in the ER lumen.…”