Gierasch lab’s review in Science identifies knowledge gaps about how proteins transmit cellular signals

An invited review article by professor Lila Gierasch, Biochemistry and Molecular Biology and Chemistry, with co-author Robert Smock, a Molecular and Cellular Biology graduate student, is featured as the cover story in the April 10 issue of the journal Science.

Gierasch’s laboratory is known for creative approaches to explore mechanisms related to how a cell’s proteins fold into three-dimensional structures, respond to signals, and direct hundreds or thousands of complex interactions. Gierasch and Smock’s review specifically discusses emerging ideas on how the intrinsic, dynamic properties of signaling proteins allow them to act as receivers, switches, relays and nodes along pathways inside and outside cells and across cell membranes. Signals are constantly being sensed by cellular networks and are crucial to cellular functions, they note. “A central tenet is that proteins fluctuate among many states on evolutionarily selected energy landscapes.” Energy landscapes refer to the many chemical interactions genetically encoded in proteins and how these lead proteins to fold into their effective or active states.

Gierasch and Smock say “a huge gap” exists at present between understanding the molecular and cellular or intercellular levels of signaling. They point out that “new methods provide insight into the dynamic properties of signaling proteins at the atomic scale. The next stages in the signaling hierarchy—how multiple signals are integrated and how cellular signaling pathways are organized in space and time—present exciting challenges for the future, requiring bold multidisciplinary approaches.” Using several recently studied signaling systems as illustrations, the biochemists discuss how proteins’ intrinsic properties allow them to act as switches and transducers of incoming signals and then respond.

The reviewers say “explosive progress in the identification of components in signaling networks and the mapping of their interactions provides a tantalizing challenge for the future.” But in their opinion, progress will require “powerful new methods, interdisciplinary strategies, and creative, bold minds.” Among current encouraging developments, Gierasch and Smock conclude, are the use of information theory to quantitatively interpret signal transmission, multiscale modeling “to move from molecular simulations to biochemical networks,” and efforts to map signaling timescales in whole cells.

April 10, 2009.

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