title: ARL15, a GTPase implicated in rheumatoid arthritis, potentially repositions its truncated N-terminus as a function of guanine nucleotide binding
creator: Saini, Manisha
creator: Upadhyay, Neelam
creator: Dhiman, Kanika
creator: Manjhi, Satish Kumar
creator: Kattuparambil, Aman Achutan
creator: Ghoshal, Antara
creator: Arya, Richa
creator: Dey, Sanjay Kumar
creator: Sharma, Aditya
creator: Aduri, Raviprasad
creator: Thelma, B. K.
creator: Ashish, Fnu
creator: Kundu, Suman
subject: QR Microbiology
description: The ADP ribosylation factor like protein 15 (ARL15) gene encodes for an uncharacterized GTPase associated with rheumatoid arthritis (RA) and other metabolic disorders. Investigation of the structural and functional attributes of ARL15 is important to position the protein as a potential drug target. Using spectroscopy, we demonstrated that ARL15 exhibits properties inherent of GTPases. The Km and Vmax of the enzyme were calculated to be 100 μM and 1.47 μmole/min/μL, respectively. The equilibrium dissociation constant (Kd) of GTP binding with ARL15 was estimated to be about eight-fold higher than that of GDP. Small Angle X-ray Scattering (SAXS) data indicated that in solution, the apo state of monomeric ARL15 adopts a shape characterized by a globe of maximum linear dimension (Dmax) of 6.1 nm, and upon binding to GTP or GDP, the vector distribution profile changes to peak-n-tail shoulder with Dmax extended to 7.6 and 7.7 nm, respectively. Structure restoration using a sequence-based template and experimental SAXS data provided the first visual insight revealing that the folded N-terminal in the unbound state of the protein may toggle open upon binding to guanine nucleotides. The conformational dynamics observed in the N-terminal region offer a scope to develop drugs that target this unique GTPase, potentially providing treatments for a range of metabolic disorders.
publisher: ELSEVIER 
date: 2024-01
type: Article
type: PeerReviewed
relation: https://www.sciencedirect.com/science/article/pii/S0141813023047979?via%3Dihub
identifier:   Saini, Manisha and Upadhyay, Neelam and Dhiman, Kanika and Manjhi, Satish Kumar and Kattuparambil, Aman Achutan and Ghoshal, Antara and Arya, Richa and Dey, Sanjay Kumar and Sharma, Aditya and Aduri, Raviprasad and Thelma, B. K. and Ashish, Fnu and Kundu, Suman  (2024) ARL15, a GTPase implicated in rheumatoid arthritis, potentially repositions its truncated N-terminus as a function of guanine nucleotide binding.  INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, 254 (2).       
relation: http://crdd.osdd.net/open/3135/