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Principles for Tuning Target Selectivity in Signaling Proteins

Award Number: R01GM097553
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2011
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Principles for Tuning Target Selectivity in Signaling Proteins - 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 insights into how the time and amplitude varying Ca2+ signal is decoded by CaM and the family of CaM-binding targets into coordinated biological responses.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	000	10	11/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	8	11/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $285,845 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	002	10	9/22/2022	NON-COMPETING CONTINUATION	$291,805
2022	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Biomedical Research and Research Training	001	9	9/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$51,300
2022	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	8	9/6/2022	NON-COMPETING CONTINUATION	-$57,260
														Subtotal = $285,845

Issue Date FY: 2021 ( Subtotal = $272,262 )
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	8	6/24/2021	NON-COMPETING CONTINUATION	$272,262
														Subtotal = $272,262

Issue Date FY: 2020 ( Subtotal = $272,339 )
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	7	4/9/2020	NON-COMPETING CONTINUATION	$272,339
														Subtotal = $272,339

Issue Date FY: 2019 ( Subtotal = $315,081 )
2019	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	001	6	4/24/2019	COMPETING CONTINUATION	$315,081
2019	2015	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	5	2/17/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $315,081

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	5	7/6/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $249,120 )
2015	2015	UNIVERSITY OF HOUSTON DOWNTOWN	ONE MAIN STREET	HOUSTON	TX	77002	HARRIS	USA	Biomedical Research and Research Training	000	5	9/2/2015	NON-COMPETING CONTINUATION	$249,120
														Subtotal = $249,120

Issue Date FY: 2014 ( Subtotal = $311,814 )
2014	2014	UNIVERSITY OF HOUSTON DOWNTOWN	ONE MAIN STREET	HOUSTON	TX	77002	HARRIS	USA	Biomedical Research and Research Training	000	4	9/3/2014	NON-COMPETING CONTINUATION	$311,814
														Subtotal = $311,814

Issue Date FY: 2013 ( Subtotal = $322,865 )
2013	2013	UNIVERSITY OF HOUSTON DOWNTOWN	ONE MAIN STREET	HOUSTON	TX	77002	HARRIS	USA	Biomedical Research and Research Training	000	3	8/30/2013	NON-COMPETING CONTINUATION	$322,865
														Subtotal = $322,865

Issue Date FY: 2012 ( Subtotal = $334,112 )
2012	2012	UNIVERSITY OF HOUSTON DOWNTOWN	ONE MAIN STREET	HOUSTON	TX	77002	HARRIS	USA	Biomedical Research and Research Training	000	2	8/29/2012	NON-COMPETING CONTINUATION	$334,112
														Subtotal = $334,112

Issue Date FY: 2011 ( Subtotal = $365,748 )
2011	2011	UNIVERSITY OF HOUSTON DOWNTOWN	ONE MAIN STREET	HOUSTON	TX	77002	HARRIS	USA	Biomedical Research and Research Training	000	1	9/27/2011	NEW	$365,748
														Subtotal = $365,748

Grand Total All Awards = $2,729,186

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Principles for Tuning Target Selectivity in Signaling Proteins

Award Number: R01GM097553

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2011

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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