# Principles for Tuning Target Selectivity in Signaling Proteins

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2021 · $215,002

## Abstract

Calcium (Ca2+) signaling requires Ca2+ concentration varying with time. Calmodulin (CaM) is a main target for
decoding the Ca2+ signal but its intrinsic Ca2+-binding properties alone appear insufficient to decode rapidly
fluctuating Ca2+ signals. We propose that in addition to transducing the signal downstream, CaM-targets
directly tune the Ca2+-binding properties of CaM through reciprocal interactions mediated by conformational
adjustments that add an undiscovered temporally varying mechanism for producing target selectivity. Further,
we propose that the target induced tuning of CaM's Ca2+-binding properties from the perspective of ter-
molecular reactions is the missing piece to the puzzle for how CaM selectivity is mediated. The objective of
the present proposal is to develop a novel approach characterizing how CaM binds Ca2+ and its target protein
reciprocally, which underlies the central feature of CaM's target selectivity. Work accomplished in the previous
funding period has shown that CaM binding to its targets is a process involving conformationally and mutually
induced fit and that the conformational adjustments in both CaM and target molecules must be overcome in the
pathway of binding. Our progress has built the foundation for the central hypothesis in this continuing project
that the Ca2+ in a Ca2+-binding loop tunes the local electric field and the loop conformations differentially among
the four EF-hands of CaM. The integrative dynamics of these EF hands adjusts the reciprocal relations
between CaM's Ca2+ binding and target binding, which is distinctive to a target. We further demonstrate the
principle of target selectivity with a system of two antagonist targets, neurogranin and CaM-dependent kinase II,
interacting with CaM as a module for decoding distinct patterns of Ca2+ input. The rationale is that once the
principle of tuning the reciprocal relation by a protein target is identified, we can design such protein targets
that control CaM to respond to different frequencies or amplitudes of Ca2+ for transducing signals in live cells.
We will test our central hypothesis by pursuing the following three thrusts: (1) How does the four EF hands of
CaM differentially react to a target protein and shape the global conformation of CaM under the variable
content of Ca2+-binding? (2) How does Ca2+ tune its local electric field and conformations of an EF hand in
response to target binding? (3) How does CaM select from the two competing protein targets that tune CaM's
affinity for Ca2+ in opposite directions? The research proposed is innovative because we will develop a novel
computer model for Ca2+ sensing in CaM by integrating quantum mechanical calculations, molecular
simulations, and biophysical and biochemical experiments, to characterize how target selectivity can be
achieved. The proposed research is of significance because the proposed study would engender a
breakthrough in our understanding of these processes and will provide insight...

## Key facts

- **NIH application ID:** 10142487
- **Project number:** 5R01GM097553-08
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** Margaret Shun Cheung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $215,002
- **Award type:** 5
- **Project period:** 2011-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142487

## Citation

> US National Institutes of Health, RePORTER application 10142487, Principles for Tuning Target Selectivity in Signaling Proteins (5R01GM097553-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142487. Licensed CC0.

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