Pre-Lamin A/C

Pre-Lamin A/C

Pre-Lamin A/C is a precursor protein that is processed to form Lamin A and Lamin C, which are essential components of the nuclear lamina, a dense fibrillar network inside the nucleus of most cells. These proteins are encoded by the LMNA gene and play a critical role in maintaining the structural integrity of the nucleus, regulating gene expression, and facilitating DNA replication and repair.

Structure

Pre-Lamin A/C is initially synthesized as a single polypeptide chain. The LMNA gene undergoes alternative splicing to produce two main isoforms: Lamin A and Lamin C. Pre-Lamin A contains a C-terminal CAAX motif, which undergoes a series of post-translational modifications, including farnesylation, proteolytic cleavage, and methylation, to become mature Lamin A. Lamin C, on the other hand, lacks the CAAX motif and does not undergo these modifications.

Function

Pre-Lamin A/C, through its mature forms, Lamin A and Lamin C, contributes to the mechanical stability of the nucleus. It interacts with other nuclear envelope proteins and chromatin, influencing nuclear shape and size. Lamin A/C is also involved in the regulation of gene expression by interacting with transcription factors and chromatin-modifying complexes.

Clinical Significance

Mutations in the LMNA gene can lead to a group of disorders known as laminopathies. These include Hutchinson-Gilford Progeria Syndrome, Emery-Dreifuss Muscular Dystrophy, and Dilated Cardiomyopathy. These conditions are characterized by defects in nuclear structure and function, leading to a wide range of clinical manifestations.

Processing of Pre-Lamin A

The processing of Pre-Lamin A involves several steps:

1. Farnesylation: Addition of a farnesyl group to the cysteine residue in the CAAX motif. 2. Proteolytic Cleavage: Removal of the last three amino acids (AAX) by the enzyme ZMPSTE24. 3. Methylation: Methylation of the farnesylated cysteine. 4. Second Proteolytic Cleavage: Removal of the farnesylated cysteine by ZMPSTE24, resulting in mature Lamin A.

Defects in this processing pathway, particularly mutations affecting ZMPSTE24, can lead to the accumulation of farnesylated Pre-Lamin A, which is toxic to cells and contributes to disease pathogenesis.

Also see

• Lamin A
• Lamin C
• LMNA
• Nuclear Lamina
• Laminopathies
• Hutchinson-Gilford Progeria Syndrome