LCHN is a protein that in humans is encoded by the KIAA1147 gene (NCBI Gene ID 57189) located on chromosome 7. It is likely part of the tripartite DENN domain family of proteins that often function as Rab-GEFs to regulate vesicular trafficking. Both the mRNA and protein have been shown to be upregulated following ischemic stroke, and to be produced at altered levels in patients with FTD-ALS, however the gene's contribution to these states is not well understood.
Gene
KIAA1147 is located on the 7th chromosome in humans from bases 141652381-141702188 on the negative strand. Additional names for KIAA1147 include PRO25611, AI841796 in the mouse and RGD1563986 in the rat. Only one mRNA transcript of KIAA1147 has been reported in NCBI, and is composed of 9 exons.
Protein
Human LCHN is a cytoplasmic protein composed of 455 amino acids predicted to be 51.4 kD before modifications with isoelectric point of 5.06. The majority of its 455 amino acids make up the tripartite DENN domains which are commonly found in proteins that act as Rab-GEFs and regulate vesicular trafficking. LCHN has several predicted phosphorylation sites and contains many motifs for kinase binding. The uDENN and cDENN domains of LCHN are predicted to be primarily coil, while the dDENN domain is predicted to be a combination of alpha helix and beta sheet. The cDENN domain is the most highly conserved domain within DENN family proteins, and is also primarily coil in protein DENND1B, which has been crystallized and confirmed to interact with the guanine nucleotide exchange domain of Rab-35. LCHN also contains a Stability of Polarity Axis (SPA) region. that may allow it to play a role in cell division.
Expression
Tissues
The Human Protein Atlas reports high levels of KIAA1147 transcription in several brain regions including cerebral cortex, cerebellum, and retina, as well as non-brain regions including spleen, thymus, stomach, prostate, lung, and ascending colon. Immunohistochemistry has shown LCHN to be localized to the cytoplasmic face of the Golgi apparatus in cell culture, and the brain in mouse fetal development. In the adult mouse and human brain, LCHN is expressed relatively ubiquitously. Expression of LCHN has been shown to increase in response to chronic alcoholism, immature and mature dendritic response to hypoxia, and ischemic stroke.
Transcriptional regulation
There are binding sites for two main groups of transcription factors in the predicted promoter of KIAA1147. The first group consists of elements related to the cell cycle and neuronal development and includes AP-2, NRF1, BRAC, E2F, NEUR, and NRSF. The second consists of elements related to brain insult, including HIFF (hypoxia inducible factor), CREB (cAMP responsive factor linked to ER stress response), GREF (glucocorticoid responsible factor), HEAT (heat shock responsive factor), and HDBP (Huntington's disease regulatory binding protein). In patients with FTD-ALS, there has been reported abnormal upstream CpG methylation of KIAA1147
Interacting proteins
SETBP1
Yeast two-hybrid assays have shown LCHN to physically interact with SETBP1, a protein that contains 3 nuclear localization signals. Despite the lack of a predicted nuclear localization signal in its own sequence, this interaction suggests that LCHN may be able to enter and have functional importance in the nucleus.
TGOLN2
In affinity chromatography studies, LCHN has been reported to have a physical association with TGOLN2, a surface protein of the Golgi apparatus. This likely explains immunohistochemical finding of strong LCHN localization near the Golgi apparatus despite being a predicted cytoplasmic protein.
Kallikreins
Affinity chromatography studies have also reported a physical association between LCHN and kallikreins KLK5 and KLK11, serine proteases. It is possible that cleavage by these proteases may be relevant to LCHN's function.
EFNB3
LCHN has been reported to be capable of a physical association with EFNB3, an ephrin receptor ligand with reported importance in neuronal development. This, coupled with the high expression of LCHN in the developing central nervous system, suggests that binding of LCHN to EFNB3 may modulate neuronal development.