HSP90AA1

Official Full Name

heat shock protein 90 alpha family class A member 1

Organism

Homo sapiens

GeneID

3320

Background

The protein encoded by this gene is an inducible molecular chaperone that functions as a homodimer. The encoded protein aids in the proper folding of specific target proteins by use of an ATPase activity that is modulated by co-chaperones. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Synonyms

EL52; HSPN; LAP2; HSP86; HSPC1; HSPCA; Hsp89; Hsp90; LAP-2; HSP89A; HSP90A; HSP90N; Hsp103; HSPCAL1; HSPCAL4; HEL-S-65p;

Bio Chemical Class

Heat shock protein

Protein Sequence

MPEETQTQDQPMEEEEVETFAFQAEIAQLMSLIINTFYSNKEIFLRELISNSSDALDKIRYESLTDPSKLDSGKELHINLIPNKQDRTLTIVDTGIGMTKADLINNLGTIAKSGTKAFMEALQAGADISMIGQFGVGFYSAYLVAEKVTVITKHNDDEQYAWESSAGGSFTVRTDTGEPMGRGTKVILHLKEDQTEYLEERRIKEIVKKHSQFIGYPITLFVEKERDKEVSDDEAEEKEDKEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEELNKTKPIWTRNPDDITNEEYGEFYKSLTNDWEDHLAVKHFSVEGQLEFRALLFVPRRAPFDLFENRKKKNNIKLYVRRVFIMDNCEELIPEYLNFIRGVVDSEDLPLNISREMLQQSKILKVIRKNLVKKCLELFTELAEDKENYKKFYEQFSKNIKLGIHEDSQNRKKLSELLRYYTSASGDEMVSLKDYCTRMKENQKHIYYITGETKDQVANSAFVERLRKHGLEVIYMIEPIDEYCVQQLKEFEGKTLVSVTKEGLELPEDEEEKKKQEEKKTKFENLCKIMKDILEKKVEKVVVSNRLVTSPCCIVTSTYGWTANMERIMKAQALRDNSTMGYMAAKKHLEINPDHSIIETLRQKAEADKNDKSVKDLVILLYETALLSSGFSLEDPQTHANRIYRMIKLGLGIDEDDPTADDTSAAVTEEMPPLEGDDDTSRMEEVD

Open

Disease

Acute upper respiratory infection, Alzheimer disease, Asthma, Breast cancer, Diabetes mellitus, Encephalopathy, Lung cancer, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature B-cell lymphoma, Melanoma, Multiple myeloma, Neuropathy, Ovarian cancer, Renal cell carcinoma, Solid tumour/cancer, Stomach cancer, Unspecific body region injury, Vasomotor/allergic rhinitis

Approved Drug

2 +

Clinical Trial Drug

16 +

Discontinued Drug

4 +

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Detailed Information

The heat shock protein 90 alpha (Hsp90α) is encoded by the important gene HSP90AA1. Hsp90α is involved in cellular stress responses and many important cellular processes. This molecular chaperone is very important for keeping client proteins stable and folded. Some of these proteins are very important for controlling the cell cycle and sending signals. It is written on the complement strand of Chromosome 14q32.33 and is over 59 kbp long. There are many fake genes spread out in the genome on Chromosomes 3, 4, 11, and 14. Cancer is just one of many diseases that this protein is linked to. It is also involved in controlling how cells respond to stress.

Gene Structure and Transcription

Two different mRNA transcripts are made by the HSP90AA1 gene. They are called Transcript Variant 1 (TV1) and Transcript Variant 2 (TV2). TV1, also called NM_001017963.2, stands for a version of the protein that is only found in primates. It is made up of 854 amino acids. This version is bigger because it has an extra 112 amino acids at the N-terminus. But it's still not clear what this extra domain does. TV2, or NM_005348.3, codes for the 732 amino acid version that has been studied a lot. It is 122 amino acids shorter than TV1. This version and the other one are made by two different transcription start sites (TSS). Even though they are structurally different, they mostly do the same thing, which is to help molecules stick together.

Figure 1 shows the transcription start sites of the HSP90AA1 gene, where RNA polymerase II binds at three distinct locations—two linked to Transcript Variant 2 and one linked to Transcript Variant 1, based on data from UCSC Genome Browser and Encode. Figure 1. Depiction of the HSP90AA1 transcription start sites. (Zuehlke AD, et al., 2015)

Transcription of HSP90AA1 is primarily induced by cellular stress through the heat shock transcription factor HSF1. The HSP90AA1 promoter region contains multiple heat shock elements (HSE), critical for the induction of gene expression under stress conditions. While HSF1 binding to these elements is well-documented, other transcription factors such as MYC and STAT5 also play significant roles in regulating HSP90AA1 expression. Notably, MYC has been shown to induce HSP90AA1 expression in cancer cells, suggesting its involvement in tumorigenesis.

Molecular Function and Role in Cellular Processes

HSP90AA1 is a molecular chaperone that functions as a homodimer, facilitating the proper folding of client proteins through its ATPase activity. This activity is modulated by a set of co-chaperones, which guide the recognition of specific substrates and help drive conformational changes in the client proteins. These conformational changes activate the client proteins, allowing them to perform their biological functions. Beyond its chaperone role, HSP90AA1 also plays a critical part in regulating transcription machinery. It interacts with transcription factors and epigenetic regulators to modulate gene expression in response to physiological cues.

One of the key features of Hsp90α is its involvement in maintaining the stability of oncogenic proteins, which are often overexpressed in cancer cells. These include proteins like c-Src, Raf-1, and Akt, which are important for cellular growth and survival. HSP90AA1 has been linked to various cancer-related processes, such as drug resistance, tumor progression, and metastasis. Indeed, Hsp90 inhibitors are currently being explored as potential cancer therapies, targeting this protein to destabilize oncogenic proteins and inhibit tumor growth. However, because HSP90 exists in several isoforms, developing selective inhibitors for the Hsp90α isoform remains a challenge.

In addition to its chaperone activity, HSP90AA1 is also involved in the regulation of mitochondrial protein import. It delivers preproteins to the mitochondrial receptor TOMM70, a process essential for maintaining mitochondrial function. Furthermore, HSP90AA1 participates in cellular responses to inflammatory stimuli. It can bind bacterial lipopolysaccharide (LPS), triggering an inflammatory response by promoting TNF secretion in monocytes. This function is particularly relevant in the context of infections and immune responses.

Regulation and Implications in Disease

Several transcription factors tightly control the production of the HSP90AA1 gene. The gene is always produced in normal situations, but its expression goes up when stress is present or when cancer pathways are activated. A lot of different transcription factors and communication channels work together to control this. For instance, the proto-oncogene MYC can directly bind to the HSP90AA1 promoter to enhance its expression, particularly in cancer cells. On the other hand, factors like STAT1, known for its tumor-suppressive activity, can suppress the stress-induced expression of HSP90AA1.

The role of HSP90AA1 in diseases, especially cancer, has led to significant research into its potential as a therapeutic target. Overexpression of Hsp90α is often associated with aggressive cancer phenotypes, including increased resistance to chemotherapy and radiation. In cancers such as breast and ovarian cancer, growth factors like prolactin have been shown to induce HSP90AA1 expression through signaling pathways such as STAT5. The pro-survival properties of HSP90AA1, particularly through its interaction with NF-kB, contribute to its role in sustaining the viability of cancer cells under stress conditions.

Research has also indicated that the degradation of client proteins due to the knockdown of Hsp90α results in the loss of oncogenic transformation, further supporting the potential of Hsp90α-selective inhibitors as therapeutic agents. Targeting the Hsp90α isoform specifically offers a promising strategy for cancer treatment, particularly because of its crucial involvement in maintaining the stability of oncogenic proteins.

References:

Zuehlke AD, Beebe K, Neckers L, et al. Regulation and function of the human HSP90AA1 gene. Gene. 2015;570(1):8-16.
Xue Nina, Jin Jing, Chen Xiaoguang. Co-chaperones: regulated action in conformational functions of HSP90 and their actions in cancer. Acta Pharmacol. Sin. 2017, 52, 1085-1090.
Anuj Khandelwal, Caitlin N. Kent, et al. Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor. Nat. Commun. 2018, 9, 425.

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