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Structural Analysis of the Mannose 6-Phosphate Receptors

Award Number: R01DK042667
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/1992
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Structural Analysis of the Mannose 6-Phosphate Receptors - Lysosomes perform degradative metabolism critical to many endocytic, phagocytic, and autophagic processes. Cation-independent mannose 6-phosphate receptor (CI-MPR) plays a vital role in the biogenesis of lysosomes by delivering ~60 different newly synthesized hydrolytic enzymes with mannose 6-phosphate (M6P) on their N-glycans to lysosomes. Lysosomal storage diseases (LSDs) are caused by mutations in lysosomal proteins, mainly enzymes, that result in defective catabolism and substrate accumulation. Characteristic of the family of ~70 LSDs is their progressive and debilitating nature due to their impact on multiple organ systems. Treatment is symptomatic for most LSDs, with only 11 having FDA-approved therapies. CI-MPR's ability to internalize recombinant M6P- containing enzymes delivered to patients by bi-weekly intravenous infusion forms the basis of enzyme replacement therapy (ERT) for 9 of these therapies. However, structural knowledge of the interaction between CI-MPR and its cargo of ~60 different lysosomal enzymes is lacking. CI-MPR also binds a diverse set of extracellular non-M6P-containing ligands that mediate CI-MPR's tumor suppressor role and regulation of cell growth and differentiation. CI-MPR regulates plasma insulin-like growth factor 2 (IGF2) levels, and binds three components of the plasminogen activation system, plasminogen, urokinase-type plasminogen activator receptor (uPAR), and tissue-type PA (tPA). However, limited information is available concerning the molecular basis for CI-MPR's interaction with plasminogen and uPAR. Here we will expand upon our preliminary data that: 1) revealed the crystal structure of CI- MPR's N-terminal region that houses several ligand binding sites, 2) showed the first structural view of CI-MPR's entire extracellular region by high-resolution electron microscopy (EM), and 3) identified conformational changes elicited by pH and ligand binding. The overall structure of CI-MPR's 2300- residue extracellular region comprised of 15 domains will be determined alone and bound to ligands using an integrated approach combining single particle EM, mass spectrometry, X-ray crystallography and NMR spectroscopy. The first structure of a complex between CI-MPR and a lysosomal enzyme (Aim 1), plasminogen (Aim 2), and uPAR (Aim 2) will be elucidated. Kinetic analyses and cell-based assays will evaluate allosteric effects of each of CI-MPR's ligands (Aim 2). The mechanism of acidic pH-dependent ligand dissociation, which is essential to the functioning of CI-MPR and other endocytic receptors, will be probed using mutagenesis studies and NMR techniques (Aim 3). Our new rat model of the LSD Fabry disease will be used to test novel lysosomal enzyme-IGF2 fusion constructs for their ability to reduce substrate accumulation (Aim 4). These studies will provide insight for the design of improved therapeutics for the treatment of LSDs, and novel inhibitors of plasminogen activation.


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 = -$109,082 )
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	9/18/2024	NON-COMPETING CONTINUATION	-$109,082
														Subtotal = -$109,082

Issue Date FY: 2023 ( Subtotal = $603,367 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	1/5/2023	NON-COMPETING CONTINUATION	$603,367
														Subtotal = $603,367

Issue Date FY: 2022 ( Subtotal = $609,491 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	28	4/25/2022	NON-COMPETING CONTINUATION	$60,950
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	28	12/29/2021	NON-COMPETING CONTINUATION	$548,541
														Subtotal = $609,491

Issue Date FY: 2021 ( Subtotal = $614,643 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	27	2/5/2021	NON-COMPETING CONTINUATION	$61,465
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	1/8/2021	NON-COMPETING CONTINUATION	$553,178
														Subtotal = $614,643

Issue Date FY: 2020 ( Subtotal = $657,891 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	26	12/18/2019	COMPETING CONTINUATION	$657,891
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	26	5/29/2020	COMPETING CONTINUATION	$301,879
2020	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	12/17/2019	NON-COMPETING CONTINUATION	$0
2020	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	25	5/29/2020	NON-COMPETING CONTINUATION	-$301,879
														Subtotal = $657,891

Issue Date FY: 2019 ( Subtotal = $601,437 )
2019	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	12/3/2018	NON-COMPETING CONTINUATION	$601,437
														Subtotal = $601,437

Issue Date FY: 2018 ( Subtotal = $601,437 )
2018	2018	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	24	4/23/2018	NON-COMPETING CONTINUATION	$60,143
2018	2018	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	11/27/2017	NON-COMPETING CONTINUATION	$541,294
														Subtotal = $601,437

Issue Date FY: 2017 ( Subtotal = $601,437 )
2017	2017	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	11/28/2016	NON-COMPETING CONTINUATION	$541,294
2017	2017	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	6/15/2017	NON-COMPETING CONTINUATION	$60,143
														Subtotal = $601,437

Issue Date FY: 2016 ( Subtotal = $624,502 )
2016	2016	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	11/17/2015	COMPETING CONTINUATION	$624,502
2016	2014	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	11/16/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $624,502

Issue Date FY: 2014 ( Subtotal = $455,674 )
2014	2014	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	4/21/2014	NON-COMPETING CONTINUATION	$455,674
														Subtotal = $455,674

Issue Date FY: 2013 ( Subtotal = $439,725 )
2013	2013	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	5/13/2013	NON-COMPETING CONTINUATION	$439,725
														Subtotal = $439,725

Issue Date FY: 2012 ( Subtotal = $455,674 )
2012	2012	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	4/23/2012	NON-COMPETING CONTINUATION	$455,674
														Subtotal = $455,674

Issue Date FY: 2011 ( Subtotal = $525,576 )
2011	2011	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	6/3/2011	COMPETING CONTINUATION	$78,836
2011	2011	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	2/1/2011	COMPETING CONTINUATION	$446,254
2011	2011	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	2/11/2011	COMPETING CONTINUATION	$486
														Subtotal = $525,576

Issue Date FY: 2010 ( Subtotal = $37,571 )
2010	2010	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Trans-NIH Recovery Act Research Support	000	17	12/28/2009	SUPPLEMENT FOR EXPANSION	$37,571
2010	2009	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	4/15/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $37,571

Issue Date FY: 2009 ( Subtotal = $328,568 )
2009	2009	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Trans-NIH Recovery Act Research Support	001	17	6/5/2009	SUPPLEMENT FOR EXPANSION	$11,821
2009	2009	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	4/22/2009	NON-COMPETING CONTINUATION	$316,747
														Subtotal = $328,568

Issue Date FY: 2008 ( Subtotal = $316,747 )
2008	2008	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	3/18/2008	NON-COMPETING CONTINUATION	$316,747
														Subtotal = $316,747

Issue Date FY: 2007 ( Subtotal = $323,212 )
2007	2007	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/23/2007	NON-COMPETING CONTINUATION	$323,212
														Subtotal = $323,212

Issue Date FY: 2006 ( Subtotal = $332,865 )
2006	2006	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	4/20/2006	NON-COMPETING CONTINUATION	$332,865
														Subtotal = $332,865

Issue Date FY: 2005 ( Subtotal = $340,875 )
2005	2005	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	2/21/2005	COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Grand Total All Awards = $9,973,656

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Structural Analysis of the Mannose 6-Phosphate Receptors

Award Number: R01DK042667

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/1992

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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