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Title: Crystal structure of the WD40 domain dimer of LRRK2

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [2];  [1];  [1];  [1];  [3];  [2];  [1]
  1. Harvard Medical School, Boston, MA (United States); Boston Children’s Hospital, Boston, MA (United States)
  2. University of Dundee (United Kingdom)
  3. Univ. of California, San Diego, La Jolla, CA (United States)
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Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein with both a Ras of complex (ROC) domain and a kinase domain (KD) and, therefore, exhibits both GTPase and kinase activities. Human genetics studies have linked LRRK2 as a major genetic contributor to familial and sporadic Parkinson’s disease (PD), a neurodegenerative movement disorder that inflicts millions worldwide. The C-terminal region of LRRK2 is a Trp-Asp-40 (WD40) domain with poorly defined biological functions but has been implicated in microtubule interaction. Here, we present the crystal structure of the WD40 domain of human LRRK2 at 2.6-Å resolution, which reveals a seven-bladed WD40 fold. The structure displays a dimeric assembly in the crystal, which we further confirm by measurements in solution. We find that structure-based and PD-associated disease mutations in the WD40 domain including the common G2385R polymorphism mainly compromise dimer formation. Assessment of full-length LRRK2 kinase activity by measuring phosphorylation of Rab10, a member of the family of Rab GTPases known to be important kinase substrates of LRRK2, shows enhancement of kinase activity by several dimerization-defective mutants including G2385R, although dimerization impairment does not always result in kinase activation. Furthermore, mapping of phylogenetically conserved residues onto the WD40 domain structure reveals surface patches that may be important for additional functions of LRRK2. Collectively, our analyses provide insights for understanding the structures and functions of LRRK2 and suggest the potential utility of LRRK2 kinase inhibitors in treating PD patients with WD40 domain mutations.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); Michael J. Fox Foundation for Parkinson’s Research; Medical Research Council; National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357; 11211; 6986; MC_UU_12016/2; P30 GM124165; S10 RR029205
OSTI ID:
1558309
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 5; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 37 works
Citation information provided by
Web of Science

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Cited By (2)

Kinase Domain Is a Dynamic Hub for Driving LRRK2 Allostery journal October 2020
The Michael J. Fox Foundation for Parkinson’s Research Strategy to Advance Therapeutic Development of PINK1 and Parkin journal July 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
biological sciences
biochemistry
LRRK2
WD40
crystal structure
Parkinson's disease