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Molecular characterization of cardiomyopathy mutations in human cardiac myosin

Award Number: R01HL117138
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2013
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Molecular characterization of cardiomyopathy mutations in human cardiac myosin - PROJECT SUMMARY / ABSTRACT The 10-member sarcomeric myosin heavy chain gene family has been studied extensively and mutations in half of its members have been implicated in disease. Myosin motors convert chemical energy into mechanical force by amplifying the ATP-driven conformational rotation of myosin’s lever arm, which consists of a helical pliant region and the α-helix of the heavy chain stabilized and stiffened by essential and regulatory light chains; hereafter referred to as the lever arm. While a great deal of study has been devoted to the catalytic domain and converter, the lever arm has often been treated as simply a semi-rigid extension of the converter to amplify the stroke size of the motor. For a given isoform of myosin the entire lever arm is highly conserved across species, but it is highly variant amongst the 10 isoforms, suggesting that the sequences of lever arm α- helices confer specific functions. Given the high sequence conservation of the β-cardiac lever arm across species and the high density of pathogenic mutations in it, we hypothesize that this region is an important regulatory domain that modulates myosin function and testing that hypothesis is the focus of this proposal. We propose an interdisciplinary collaboration among the Spudich, Perkins and Leinwand laboratories to study the effects of disease-causing mutations in the lever arm by integrating the biophysical characterization of isolated lever arms and myosin motor functional assays with cardiac cell biology. In the previous grant period, the Leinwand, Spudich and Geeves laboratories produced and characterized a number of disease-causing mutations of the human β-cardiac myosin motor for their biochemical and kinetic properties, but none of these studies included lever arm mutations. Because of clinical hypercontractility of hypertrophic cardiomyopathy (HCM) patients and hypocontractility of dilated cardiomyopathy (DCM) patients, we hypothesize that HCM mutations will most likely increase the stiffness of the lever arm, whereas, DCM mutations will cause the lever arm to be less stiff. In Aim I, we will determine the biochemical and mechanical properties of the lever arm of WT β-myosin using atomic force microscopy (AFM). AFM has emerged as a powerful tool for investigating the elasticity of proteins in addition to probing their folding/unfolding dynamics. Until now, AFM technology did not have the resolution to study the mechanics of the 9-nm long lever arm. However, the Perkins lab’s recent advances in single-molecule AFM techniques will enable us to compare the mechanical properties of the WT ß-cardiac myosin lever arm α-helix to ones carrying cardiomyopathy-causing mutations. In Aim II, we will measure the impact of the lever arm mutations on in vitro subfragment-1 (S1) motor function using ATPase, gliding filament and optical tweezer assays. Finally, in Aim III we will integrate these biophysical and biomechanical findings into cells by introducing WT and lever arm mutant full length β-cardiac myosins into cardiac myocytes and determining their effects on sarcomere integrity, sarcomere dynamics and contractility.


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: 2024 ( Subtotal = -$1,851 )
2024	2021	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	8	12/1/2023	NON-COMPETING CONTINUATION	-$1,851
														Subtotal = -$1,851

Issue Date FY: 2021 ( Subtotal = $577,835 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	001	8	5/18/2021	NON-COMPETING CONTINUATION	$57,784
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	8	1/21/2021	NON-COMPETING CONTINUATION	$520,051
														Subtotal = $577,835

Issue Date FY: 2020 ( Subtotal = $583,148 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	7	1/17/2020	NON-COMPETING CONTINUATION	$553,991
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	001	7	3/7/2020	NON-COMPETING CONTINUATION	$29,157
														Subtotal = $583,148

Issue Date FY: 2019 ( Subtotal = $588,305 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	6	1/8/2019	NON-COMPETING CONTINUATION	$588,305
														Subtotal = $588,305

Issue Date FY: 2018 ( Subtotal = $706,139 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Cardiovascular Diseases Research	002	5	2/3/2018	COMPETING CONTINUATION	$606,039
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	005	5	9/7/2018	SUPPLEMENT FOR EXPANSION	$100,100
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	004	5	3/1/2018	COMPETING CONTINUATION	$147,312
2018	2016	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	003	4	3/1/2018	EXTENSION WITH OR WITHOUT FUNDS	-$147,312
2018	2016	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	001	4	2/2/2018	EXTENSION WITH OR WITHOUT FUNDS	$74
2018	2015	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	3	2/2/2018	NON-COMPETING CONTINUATION	-$74
														Subtotal = $706,139

Issue Date FY: 2016 ( Subtotal = $431,278 )
2016	2016	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	4	5/20/2016	EXTENSION WITH OR WITHOUT FUNDS	$431,278
														Subtotal = $431,278

Issue Date FY: 2015 ( Subtotal = $427,578 )
2015	2015	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	3	4/23/2015	NON-COMPETING CONTINUATION	$427,578
														Subtotal = $427,578

Issue Date FY: 2014 ( Subtotal = $425,727 )
2014	2014	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	2	5/1/2014	NON-COMPETING CONTINUATION	$425,727
														Subtotal = $425,727

Issue Date FY: 2013 ( Subtotal = $430,538 )
2013	2013	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	1	8/19/2013	NEW	$430,538
														Subtotal = $430,538

Grand Total All Awards = $4,168,697

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Molecular characterization of cardiomyopathy mutations in human cardiac myosin

Award Number: R01HL117138

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/20/2013

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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