PDBsum entry 6hdu

Signaling protein

PDB id: 6hdu

Contents

Protein chains

172 a.a.

Ligands

GTP ×4

Metals

_MG ×4

Waters ×700

PDB id:

6hdu

Name:

Signaling protein

Title:

Crystal structure of human rab38 in complex with gtp

Structure:

Ras-related protein rab-38. Chain: a, b, c, d. Synonym: melanoma antigen ny-mel-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rab38. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.79Å R-factor: 0.190 R-free: 0.212

Authors:

E.Mcgrath,D.Waschbusch,A.R.Khan

Key ref:

E.McGrath et al. (2021). LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain. Small GTPases, 12, 133-146. PubMed id: 31552791 DOI: 10.1080/21541248.2019.1666623

Date:

19-Aug-18 Release date: 28-Aug-19

Protein chains

P57729  (RAB38_HUMAN) -  Ras-related protein Rab-38 from Homo sapiens

Seq: 211 a.a.

Struc: 172 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1080/21541248.2019.1666623

Small GTPases 12:133-146 (2021)

PubMed id: 31552791

LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain.

E.McGrath, D.Waschbüsch, B.M.Baker, A.R.Khan.

ABSTRACT

LRRK2 is a multi-domain Ser/Thr kinase that is associated with inherited and sporadic cases of Parkinson's disease. Many mutations linked to disease are associated within a central ROC-COR regulatory region and the subsequent kinase domain, leading to enhanced catalytic activity. The N-terminus of human LRRK2 consists of armadillo repeat motifs (ARMs) followed by ankyrin repeats (ANKs). Recently, Rab GTPases have emerged as key players in LRRK2 function, both as substrates of the kinase, and as regulators of the catalytic activity. Rabs recruit effector proteins via their GTP-dependent switch 1 and 2 regions to distinct sub-cellular compartments to regulate membrane trafficking. LRRK2 phosphorylates Rab8, Rab10 and Rab12 in switch 2, and this activity is regulated via interactions with Rab29. Furthermore, the related Rab32-subfamily GTPases, Rab32 and Rab38, have also been shown to interact with LRRK2. Here, we have mapped the interactions of the Rab32-subfamily to the ARM domain of LRRK2. The complexes are dependent on the GTP state of the Rabs in vitro, implying that LRRK2 may be an effector of the Rab32-subfamily of small GTPases. X-ray crystal structures of the Rab32-family GTPases and subsequent mutational studies reveal that a positively charged residue in switch 1 is critical for binding of Rab32/38 to LRRK2. Homology modelling and mutational analyses of the ARM domain point to a patch of negatively charged residues that contribute to complex formation. These structural and biochemical studies provide a framework for understanding the molecular basis for Rab regulation of LRRK2 and its role in Parkinson's disease.