Konark Mukherjee presents evidence that molecules believed to be benign have an active, important role in neurogenesis

Konark Mukherjee
Konark Mukherjee, PhD, assistant professor at the Virginia Tech Carilion Research Institute

Peer into the microscopic world of human biology and you’ll see an intricate dance of interactions among myriad proteins, enzymes, amino acids, and other molecules. And just like any high school prom, you’ll find wallflowers observing from the sidelines as the rest bring life to the party. Some of those bystanders, however, may not as shy as they seem.

Protein kinases are enzymes that control a wide variety of processes within a cell by modifying the activity of specific proteins and transmitting signals within virtually every cell type throughout the body. While more than 500 different kinases have been identified in human biology, some of them have been labeled “pseudokinases” because of an apparent lack of the molecular tools required to affect proteins. But as biologists learn more about life’s fundamental processes, it is becoming clear that many of these pseudokinases play important roles through nontraditional means.

The Biochemical Society recently convened a conference, “Exploring Kinomes: Pseudokinases and Beyond,” to explore developments in the understanding of these roles. Held at Robinson College in Cambridge, United Kingdom, the gathering featured expert speakers in the field. Among the invited experts was Konark Mukherjee, assistant professor at the Virginia Tech Carilion Research Institute and in the Department of Biological Sciences at Virginia Tech.

“The rest of the speakers were absolutely a ‘who’s who’ of the kinase world,” said Mukherjee, who studies the roles of kinases in neurodevelopment. “I felt honored to be invited.”

Mukherjee’s research focuses on a specific class of protein kinases called membrane-associated guanylate kinases (MAGUKs), which help produce proteins that provide scaffolding on which neurons grow. One specific type of MAGUK, called calcium/calmodulin-dependent serine protein kinase (CASK), was labeled a pseudokinase years ago because of its inability to bind with magnesium ions, a necessity for most enzymes to interact with proteins. Recent results from Mukherjee’s laboratory, however, have shown that this label is misleading, as CASK is actually quite active in the growing of neurons.

Despite its inability to bind with magnesium ions, CASK can act on at least one other molecule – the synaptic protein neurexin-1. CASK combines a role of building synaptic scaffolding with an unusual ability to act on substrates recruited to grow neurons. It appears to play an important role in pruning and refining transient neural connections. Such processes are fundamental to many components of the brain’s normal early development and susceptible to genetic and environmental perturbations that can lead to developmental disabilities.

Mukherjee’s talk focused on the evolution of the CASK gene, the various forms it takes in different animals, the underlying structural mechanisms that give rise to its unique functions, and its association with human diseases. Mutations in CASK are often affiliated with neurodevelopmental disorders such as X-linked intellectual disability.

“Being invited to present at this conference is well-deserved recognition for Konark’s contributions to this important area of brain research,” said Michael Friedlander, executive director of the VTC Research Institute. “Besides representing the research institute to the best minds in his field, Konark’s work will help us understand first principles of brain development and potential new therapeutic targets for several types of intellectual disability. Konark’s innovative and multi-scale approaches to brain development contribute to the institute’s lively interdisciplinary environment, and we’re all very proud to have him as a colleague.”

Written by Ken Kingery