HSPA9

Case Study 1: Paulo Roberto Dores-Silva, 2020

Mitochondrial Hsp70 (HSPA9, mtHsp70, mortalin) in conjunction with a complex set of other proteins is involved in the transport of polypeptides across the mitochondrial matrix. This observation allows us to hypothesize that HSPA9 might interact with membranes directly, similarly to other Hsp70s. Thus, the researchers investigated whether human HSPA9 could also get inserted into lipid membranes. Human HSPA9 was incubated with liposomes made of lipids found within the mitochondrial membrane, such as 1', 3'-bis [1, 2-dimyristoyl-sn-glycero-3-phospho]-glycerol (CL), palmitoyl-oleoyl phosphocholine (POPC), palmitoyl-oleoyl phosphoserine (POPS), and palmitoyl-oleoyl phosphoethanolamine (POPE). HSPA9 displayed a predilection for CL and POPS, and low affinity for POPC and POPE, suggesting that the proteins have high specificity for negatively charged phospholipids. Then, liposomes were made with a composition resembling either the outer or inner mitochondrial membrane (OMM or IMM, respectively). They observed that HSPA9 has a higher affinity for IMM than OMM, which is consistent with the higher content of CL in the IMM. A comparison for the incorporation into POPS or CL liposomes by HSPA9 or HSPA1 indicated that both proteins behaved very similarly when exposed to CL liposomes, but differently with POPS liposomes, which was further corroborated by their susceptibility to proteinase K digestion after incorporation into liposomes.

Fig1. Interaction of human HSPA9 with phospholipid liposomes.

Fig2. The interaction of human HSPA9 with POPS or CL liposomes does not alter their secondary structure.

Case Study 2: D Starenki, 2015

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the rearranged during transfection (RET) proto-oncogene. For therapy of advanced MTC, the Food and Drug Administration recently approved vandetanib and cabozantinib, the tyrosine kinase inhibitors targeting RET, vascular endothelial growth factor receptor, epidermal growth factor receptor and/or c-MET. Nevertheless, not all patients respond to these drugs, demanding additional therapeutic strategies. The researchers found that mortalin (HSPA9/GRP75), a member of HSP70 family, is upregulated in human MTC tissues and that its depletion robustly induces cell death and growth arrest in MTC cell lines in culture and in mouse xenografts. These effects were accompanied by substantial downregulation of RET, induction of the tumor-suppressor TP53 and altered expression of cell cycle regulatory machinery and apoptosis markers, including E2F-1, p21(CIP1), p27(KIP1) and Bcl-2 family proteins. The investigation of the molecular mechanisms underlying these effects revealed that mortalin depletion induces transient MEK/ERK (extracellular signal-regulated kinase) activation and altered mitochondrial bioenergetics in MTC cells, as indicated by depolarized mitochondrial membrane, decreased oxygen consumption and extracellular acidification and increased oxidative stress.

Fig3. Western blot analysis of mortalin expression in total cell lysates of the human MTC cell lines, TT and MZ-CRC-1.

Fig4. Immunofluoresence analysis of mortalin localization in TT and MZ-CRC-1 cells.

Fig1. Mortalin affects proliferation and survival of MTC cells by regulating the MEK/ERK pathway and mitochondrial metabolism in MTC cells. (D Starenki, 2015)

Fig2. A two-armed mechanism model by which KSHV changes cellular energy metabolism. (Ohad Yogev, 2014)

HSPA9 involved in several pathways and played different roles in them. We selected most pathways HSPA9 participated on our site, such as RNA degradation, Tuberculosis, which may be useful for your reference. Also, other proteins which involved in the same pathway with HSPA9 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

HSPA9 has several biochemical functions, for example, ATP binding, fibroblast growth factor binding, heat shock protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by HSPA9 itself. We selected most functions HSPA9 had, and list some proteins which have the same functions with HSPA9. You can find most of the proteins on our site.

HSPA9 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with HSPA9 here. Most of them are supplied by our site. Hope this information will be useful for your research of HSPA9.

TP53; EGFR; TP73