KIBRA: A New Gateway to Learning and Memory?

Abstract

The genetic locus encoding KIBRA, a member of the WWC family of proteins, has recently been shown to be associated with human memory performance through genome-wide single nucleotide polymorphism screening. Gene expression analysis and a variety of functional studies have further indicated that such a role is biologically plausible for KIBRA. Here, we review the existing literature, illustrate connections between the different lines of evidence, and derive models based on KIBRA's function(s) in the brain that can be further tested experimentally.

Keywords: Alzheimer's disease; PKCζ; cognition; cognitive impairment; genome-wide association study (GWAS); hippocampus; memory.

Figure 1

Structural features of the human KIBRA protein. Shown are the identified domains in the KIBRA protein. WW domains are located between position 6 and 86, and cover about 40 amino acids containing two conserved tryptophan residues. WW domains are generally thought to be responsible for the interaction with various proteins that contain proline-rich sequences such as PPxY. The C2 domain is located between amino acids 655 and 783. This is a conserved membrane targeting motif composed of β-sheets. The 130 residues of C2 are involved in binding phospholipids in a calcium-dependent manner. The PKCζ binding region is located at amino acids 953–996 and contains two serine residues that can be phosphorylated by the kinase. The last four amino acids contain a PDZ binding motif.

Figure 2

Known interactors of KIBRA. Depicted are interaction partners of KIBRA identified by a number of laboratories with the respective citations given. Solid dotted lines: direct interactions that have been mapped to specific segments of the KIBRA protein; hatched broad lines: direct interactions where the location of binding is not known.