4AE9: Structure And Function Of The Human Sperm-specific Isoform Of Protein Kinase A (pka) Catalytic Subunit C Alpha 2

Protein kinase A (PKA) exists as several tissue-specific isoforms that through phosphorylation of serine and threonine residues of substrate proteins act as key regulators of a number of cellular processes. We here demonstrate that the human sperm-specific isoform of PKA named Calpha2 is important for sperm motility and thus male fertility. Furthermore, we report on the first three-dimensional crystal structure of human apo Calpha2 to 2.1 A. Apo Calpha2 displays an open conformation similar to the well-characterized apo structure of murine Calpha1. The asymmetric unit contains two molecules and the core of the small lobe is rotated by almost 13 degrees in the A molecule relative to the B molecule. In addition, a salt bridge between Lys72 and Glu91 was observed for Calpha2 in the apo-form, a conformation previously found only in dimeric or ternary complexes of Calpha1. Human Calpha2 and Calpha1 share primary structure with the exception of the amino acids at the N-terminus coded for by an alternative exon 1. The N-terminal glycine of Calpha1 is myristoylated and this aliphatic chain anchors the N-terminus to an intramolecular hydrophobic pocket. Calpha2 cannot be myristoylated and the crystal structure revealed that the equivalent hydrophobic pocket is unoccupied and exposed. Nuclear magnetic resonance (NMR) spectroscopy further demonstrated that detergents with hydrophobic moieties of different lengths can bind deep into this uncovered pocket. Our findings indicate that Calpha2 through the hydrophobic pocket has the ability to bind intracellular targets in the sperm cell, which may modulate protein stability, activity and/or cellular localization.
PDB ID: 4AE9Download
MMDB ID: 98866
PDB Deposition Date: 2012/1/9
Updated in MMDB: 2012/06
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 4AE9: monomeric; determined by author and by software (PISA)
Molecular Components in 4AE9
Label Count Molecule
Protein (1 molecule)
Camp-dependent Protein Kinase Catalytic Subunit Alpha(Gene symbol: PRKACA)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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