Details

Autor(en) / Beteiligte

• Ahn, Jinsook
• Lee, Jinwook
• Jeong, Soyeon
• Jo, Inseong
• Kang, So-mi
• Park, Bum-Joon
• Ha, Nam-Chul

Titel

Structural basis for the interaction between unfarnesylated progerin and the Ig-like domain of lamin A/C in premature aging disorders

Ist Teil von

• Biochemical and biophysical research communications, 2022-12, Vol.637, p.210-217

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Hutchinson–Gilford progeria syndrome (HGPS) is a premature aging disorder caused by C-terminally truncated lamin A, termed as the pre-progerin product. Progerin is a C-terminally farnesylated protein derived from pre-progerin, which causes nuclear deformation at the inner-nuclear membrane. As an alternative or additional mechanism, a farnesylation-independent abnormal interaction between the C-terminus of progerin and Ig-like domain has been proposed. However, the molecular mechanism underlying the role of unfarnesylated C-terminus of pre-progerin in HGPS remains largely unknown. In this study, we determined the crystal structures of C-terminal peptide of progerin and Ig-like domain of lamin A/C. Results showed that the C-terminal cysteine residue of progerin forms a disulfide bond with the only cysteine residue of the Ig-like domain. This finding suggested that unfarnesylated progerin can form a disulfide bond with the Ig-like domain in the lamin meshwork. The Alphafold2-assisted docking structure showed that disulfide bond formation was promoted by a weak interaction between the groove of Ig-like domain and the unfarnesylated C-terminal tail region of progerin. Our results provide molecular insights into the normal aging process as well as premature aging of humans. •The crystal structures of Ig-like domain of lamin A/C with C-terminal peptide of progerin.•The C-terminal cysteine residue of progerin can form a disulfide bond with the Ig-like domain.•The disulfide bond formation was promoted by a weak interaction between the groove of Ig-like domain and the unfarnesylated C-terminal tail region of progerin.