CKAP4
Cytoskeleton-associated protein 4 is a protein that in humans is encoded by the CKAP4 gene.
CKAP4 also historically known as CLIMP-63 , or just p63 is an abundant type II transmembrane protein residing predominantly in the endoplasmic reticulum of eukaryotic cells and encoded in higher vertebrates by the gene CKAP4.
Discovery
CLIMP-63 was discovered in the early 1990s as the most S-palmitoylated protein during mitosis, Nevertheless, the effect of this modification to date remains unclear. CLIMP-63 was extensively studied during the 1990s by the group of Hans-Peter Hauri which has characterized CLIMP-63's life in the ER. More recently, different groups have also reported CLIMP-63's presence at the plasma membrane acting as a ligand-activated receptor. CLIMP-63 has also now been described as a marker in different cancers.Localization, molecular functions and regulation
CLIMP-63's cellular distribution has been assessed several times in the last two decades. The protein includes a cytosolic segment composed of positively charged amino acid which might act as a preponderant motif for folding and ER localization. Furthermore, CLIMP-63 was one of the first discovered ER-shaping proteins. and is mostly known for participating in the generation and maintenance of the ER sheets This is thought to occur after dimerization of CLIMP-63's luminal COILED-COIL domains in cis and/or trans. Multimerization might in addition limit CLIMP-63's diffusion out of ER-sheets.CLIMP-63 was also shown to bind microtubules through its cytoplasmic disordered tail which might help anchoring the ER-sheets to the cytoskeleton. This is regulated by phosphorylation of at least three serine residues of CLIMP-63's cytosolic tail as phosphorylation interferes with CLIMP-63's microtubule binding capacity.
In addition, CLIMP-63 can undergo another post-translational modification, S-palmitoylation, on cysteine 100 of its cytoplasmic domain. So far only the palmitoyl-acyltransferase ZDHHC2 has been identified as a potential regulator of CLIMP-63's palmitoylation but as ZDHHC2 resides mostly at the plasma membrane, supplementary investigations are needed. The consequence of S-palmitoylation remain to be investigated but could play a role in the cell cycle as CLIMP-63's palmitoylation was reported to strongly increase during mitosis.
Finally, CLIMP-63 has been shown by different groups to serve as a cell surface receptor for various extracellular ligands, in particular for surfactant protein A in lungs alveoli, tissue plasminogen activator in vascular smooth muscle cells and for anti-proliferative factor in bladder epithelial cells of patients with interstitial cystitis disorder.