Thursday, February 15, 2007

Gene HSPA5 Encodes BiP-a Molecular Chaperone

Molecular chaperones are proteins that help other proteins to fold properly (see Heat Shock and Molecular Chaperones). The most important chaperones were indentified as heat shock proteins because they were produced following exposure of cells to excess heat. Their role in heat shock is to repair misfolded proteins and their role in normal cells is to assist in the proper folding of newly synthesized proteins.

The most important chaperone is HSP70 (Heat Shock Protein, Mr=70,000). It is present in all normal cells where it binds to polypeptide chains as they are being synthesized. Most cells contain multpile versions of HSP70. The different members of the gene family occupy different cell compartments. For example, there are distinct HSP70 chaperones in mitochondria, chloroplasts and cytoplasm.

The endoplasmic reticulum (ER) is a network of membranes within eukaryotic cells. Proteins that cross the ER membrane end up inside the ER in a special compartment that's isolated from the cytpolasm. Most of these proteins are destined to be exported from the cells in vesicles that bud off of the ER.

Proteins that need to be imported into the lumen of the ER are synthesized on the membrane surface. As they exit the ribosome tunnel they pass directly through a pore in the membane. When they reach the interior of the ER they are helped to fold by a member of the HSP70 gene family called BiP (Binding Protein) or GRP78 (Glucose Regulated Protein). BiP binds to the newly synthesized peptide while it is being made and while it is passing through the ER pore complex.

The HSP70 chaperones are interesting because of the role they play in protein synthesis but they are also interesting because they are the most highly conserved proteins in all of biology. This makes them ideal candidates for studies of molecular evolution. Several thousand sequences are available (HSP70 Sequence Database). The BiP gene in mammals is called HSPA5—a name choice made by the HUGO (Human Gene Organization) Naming Committee [HSPA5]. (HUGO tends to ignore names given to homologues in other species and choose human specific names. The gene is called BiP in most other species.)

HSPA5 is located near the end of the long arm of chromosome 9 at 9q33-q34.1 (chromosome map NCBI, chromosome map UCSC Genome Browser). The Entrez Gene Locus is GeneID=3309 and it lists 7 different independently-cloned genomic sequences and 8 full-length cDNAs. My favorite site is the SwissProt database (P11021) because it combines all the sequence information from each clone into one annotated sequence.

The HSPA5 gene has 8 exons in a relatively compact gene spread out over 6.5kb (6,500 bp). See the sequence [here]. There's nothing particularly unusial about this gene other than the fact that the introns are smaller than normal. All of the mamalian genes have the same intron/exon organization but other eukaryotic BiP genes may have fewer introns or none ar all.

The gene encodes a proein of 654 amino acid residues with a relative molecular mass of 72,300 (close to 70kDa, which is typical for HSP70's). The protein contains an N-terminal leader sequence that controls its import into the ER and a C-terminal ER retention signal that keeps it in the ER lumen. The rest of the sequence closely resemble all of the other members of the HSP70 gene family.

1 comment :

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