Research Activities of Trevor Creamer’s lab

The primary focus of the Creamer laboratory is on the function and regulation of the serine/threonine phosphatase calcineurin (CaN). CaN is ubiquitously expressed and highly conserved in all eukaryotes. As an integral component of several signaling pathways, this enzyme dephosphorylates, and thereby regulates, a number of important proteins such as the NFAT family of transcription activators, the microtubule-associated tau, and nitric oxide synthase. CaN plays central roles in neuronal signaling, cardiac growth and immune system activation. Dysregulation of CaN contributes to a number of disorders including Alzheimer’s disease, Down syndrome, mental retardation, cardiac hypertrophy, and autoimmune diseases.

CaN activity is tightly regulated by a number of other proteins. Calmodulin (CaM) binds to and activates CaN. Other proteins, including Rcan1, CHP1 and cabin/cain, are endogenous inhibitors of CaN. Yet others, such as AKAP79, serve to localize CaN to specific regions within a cell. Breakdowns in any of these regulatory systems can lead to pathologies associated with the diseases listed above. For example, Rcan1 is overexpressed as a consequence of the trisomy underlying Down syndrome. This in turn leads to inappropriate inhibition of CaN. Notably, the CaN regulatory mechanisms are poorly understood at the molecular/structural level.

Molecular understanding of calcineurin and it’s activation by Ca²⁺ and calmodulin

A disordered domain of calcineurin known as the regulatory domain is crucial in calmodulin-mediated activation.

Personnel involved:

Erik C. Cook and Trevor Creamer

Software:

Campari, Amber, Gaussian

Calcineurin’s interaction with the RCAN (regulator of calcineurin) family of inhibitors

RCAN family members contains disordered segments and are multivalent with respective to their calcineurin-binding properties. We seek a mechanistic understanding as to how the RCAN family inhibits calcineurin activity.

Personnel involved:

Erik C. Cook and Trevor Creamer

Software:

Campari, Amber, Gaussian

Calcineurin’s interaction with the microtubule-associated protein tau (also called “tau”)

Personnel involved:

Erik C. Cook and Trevor Creamer

Non-UK collaborators:

Douglas Kojetin

Software:

Campari, Amber, Gaussian

We plan on using part of our allocation time running Campari. Campari is an open-source Monte Carlo simulation suite specifically geared toward generating ensembles of intrinsically disordered proteins. Campari typically requires the use of 20 cores simultaneously per run in order to efficiently utilize temperature replica exchange routines. Additional understanding of disordered proteins bound to folded partners can be studies using the Amber suite for molecular dynamics. Amber can also be utilized for NMR and X-ray structure refinement.

Collaborator:

Erik C. Cook - University of Utah

Trevor P. Creamer is the P.I.

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