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Cell Adhesion Surprise

Patrick Doherty and Frank Walsh were among the first investigators to use molecular approaches to study cell adhesion molecules (CAMs) and how they function in regulating neurite growth. While studying NCAM, they identified a sequence in the FGF receptor (FGFR) that was homologous to sequences in N-cadherin and L1, two other CAMs that promote neurite growth. They dubbed this region the "CAM homology domain" and conducted experiments using peptides from the domain to argue that the FGFR directly interacted with the CAMs to promote neurite growth. This hypothesis was controversial, but subsequent pharmacological, genetic, and structural studies have given it support.

NCAM co-localizes with FGFR.

In this Paper of the Week, Elena Sanchez-Heras and her colleagues in Doherty's laboratory use co-immunoprecipitation and co-clustering assays to map sites on the FGFR that are required for interaction with N-cadherin and NCAM. They demonstrate for the first time that all of the major isoforms of NCAM can interact with the FGFR. Surprisingly, they also find that the interactions require an "acid box" region in the FGFR but not the CAM homology domain. This result leads to an unexpected situation in which FGFR-CAM interactions are confirmed, but a role for the CAM homology domain is excluded.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 35208-35216

Arginine Fingers Give Clamp Loader a Hand

During DNA replication, DNA polymerase is tethered to DNA via a clamp, which is placed onto the DNA by a clamp loader. In eukaryotes, the pentameric clamp loader known as replication factor C (RFC) uses energy from ATP binding and hydrolysis to recruit a clamp called proliferating cell nuclear antigen (PCNA), break one clamp interface, and topologically link the clamp to primed template DNA. RFC contains four ATP sites with four associated arginine fingers that sense ATP binding and catalyze ATP hydrolysis.

Residues in the central chamber of RFC are required for DNA binding.

In this study, Aaron Johnson and colleagues mutated the arginine fingers on RFC to determine the role of the fingers and their ATP sites in the PCNA loading mechanism. They show that none of the arginine fingers are needed for PCNA interaction and ring opening. However, their results demonstrate that certain ATP sites on RFC play distinct roles downstream of the PCNA opening. For example, the arginine finger in ATP site C is needed for RFC to bind DNA, and ATP hydrolysis in site D is specifically triggered by PCNA. The authors hypothesize that this site D hydrolysis leads to closure of PCNA around DNA.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 35531-35543

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