Sanabria research on cell cycle regulation featured in Nature Communications

CLEMSON – Clemson University College of Science physicist Hugo Sanabria’s collaborative research on a protein that is considered to be a suppressor of cancerous tumors has been featured in the journal Nature Communications.

Sanabria is co-first author of the article titled “Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation.”

Sanabria and an international team of scientists broke new ground on the structural dynamics of an intrinsically disorder protein (IDP) named p27 when bound in complex with cell division proteins.

In particular, the team studied the ternary complex of p27 with the Cdk2 tightly bound with Cyclin A. In this ternary complex, cell division progresses after several amino acids in p27 are phosphorylated, which were previously shown to be occluded in crystallographic structures. Phosphorylation is one of the ways in which cellular signaling occurs. Thus, the question that the team wanted to address from the beginning was how cell cycle could proceed if those important residues were found buried in previous structural studies.

To answer this question, the team used an integrated approach from structural, biochemical, biophysical and single‐molecule fluorescence methods, with Sanabria mostly contributing to the latter.

The team introduced the “dynamic anticipation” model, in which p27 locally dissociates for short time intervals anticipating the phosphorylation steps. In this way, p27 provides access to kinases that target those phosphorylatable residues. Only then, a series of cascade signals will lead to degradation of p27, driving cell division.

“p27 is an inhibitor of ‘Cyclin-dependent Kinases (Cdk),’ which controls cell cycle progression. As such, misregulation of p27 leads to diverse cancer types,” said Sanabria, who is an assistant professor in the department of physics and astronomy. “Single molecule fluorescence experiments like the ones we do at Clemson are uniquely positioned to study these systems because of the upmost high temporal and spatial resolution.”

Sanabria worked in collaboration with Richard Kriwacki at St. Jude Children’s Research Hospital, Claus Seidel at Heinrich Heine University in Germany, and Peter Tompa in the VIB Center for Structural Biology at the Vrije Universiteit Brussels. Other authors included Maksym Tsytlonok, Yuefeng Wang, Suren Felekyan, Katherina Hemmen, Aaron Phillips, Mi-Kung Yun, Michael Waddell, Cheon-Gil Park, Sivaraja Vaithiyalingam, Luigi Iconaru and Stephen White.