6Y30

NG domain of human SRP54 T115A mutant

Summary for 6Y30

• Entry DOI: 10.2210/pdb6y30/pdb
• Descriptor: Signal recognition particle 54 kDa protein (2 entities in total)
• Functional Keywords: srp54 ng domain, protein translocation, severe congenital neutropenia, disease mutant, rna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 66687.08

Authors

Juaire, K.D.,Wild, K.,Sinning, I. (deposition date: 2020-02-17, release date: 2020-09-23, Last modification date: 2024-01-24)

Primary citation

Juaire, K.D.,Lapouge, K.,Becker, M.M.M.,Kotova, I.,Michelhans, M.,Carapito, R.,Wild, K.,Bahram, S.,Sinning, I.
Structural and Functional Impact of SRP54 Mutations Causing Severe Congenital Neutropenia.
Structure, 29:15-, 2021

PubMed Abstract: The SRP54 GTPase is a key component of co-translational protein targeting by the signal recognition particle (SRP). Point mutations in SRP54 have been recently shown to lead to a form of severe congenital neutropenia displaying symptoms overlapping with those of Shwachman-Diamond syndrome. The phenotype includes severe neutropenia, exocrine pancreatic deficiency, and neurodevelopmental as well as skeletal disorders. Using a combination of X-ray crystallography, hydrogen-deuterium exchange coupled to mass spectrometry and complementary biochemical and biophysical methods, we reveal extensive structural defects in three disease-causing SRP54 variants resulting in critical protein destabilization. GTP binding is mostly abolished as a consequence of an altered GTPase core. The mutations located in conserved sequence fingerprints of SRP54 eliminate targeting complex formation with the SRP receptor as demonstrated in yeast and human cells. These specific defects critically influence the entire SRP pathway, thereby causing this life-threatening disease.

PubMed: 33053321
DOI: 10.1016/j.str.2020.09.008

Experimental method

X-RAY DIFFRACTION (2.65 Å)