Protein nonfolding as a regulatory phenomenon

Challenging the central dogma

Biochemistry students learn that protein folding is required for function. However, over the past 25 years, a group of nonfolding proteins that challenge the structure–function paradigm have been identified and shown to be unexpectedly prevalent.
Intrinsically disordered, or natively unfolded, proteins lack stable secondary and tertiary structures under physiological conditions, and many remain disordered even upon binding to their molecular partners. Their lack of stable structure and highly dynamic nature make them challenging to study.
Given that as much as 40 percent of the eukaryotic proteome is partially or entirely disordered, the scope of the problem and the need for new insights are enormous. This ASBMB annual meeting symposium will highlight computational and experimental advances in this research area.

Flexible recognition of binding partners

Disordered regions in proteins frequently mediate contacts with other proteins or nucleic acids. Reports that partially ordered linear motifs embedded within disordered sequences participate in these binding events are ubiquitous; so are observations of coupled folding and binding. Even so, is folding required for binding? This session will cover the binding mechanisms employed by intrinsically disordered proteins.

What makes a good protein go bad?

Disordered proteins are implicated in many human diseases. Although the loss of native, functional interactions of the disordered proteins is thought to play an important role in disease development, these native functions are poorly understood. The second session will explore the mechanisms of native functions of disordered proteins implicated in amyloidogenic neurodegenerative disease.

What does it mean to be disordered?

The absence of a cooperatively folded native state provides a negative definition for disorder but provides no insight into the diversity of natively disordered states. The third session will cover recent advances establishing clear connections between biological function and native disorder.

Trying to hit a moving target

The prevalence and functional significance of protein disorder are firmly established, but can this knowledge be translated into practical medical intervention? In the final session, we explore recent advances toward directly targeting disordered proteins with small-molecule therapeutics.
Elizabeth Rhoades
Scott Showalter
Organizers: Elizabeth Rhoades, Yale University, and Scott Showalter, Pennsylvania State University