Lamin A processing pathway (WP4299)

Homo sapiens

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All lamins, except lamin C, contain a CaaX tail. This tail is comprised of respectively cysteine, two aliphatic amino acids and any amino acid with a COOH-terminal (variable). Aliphatic amino acids are nonpolar and hydrophobic and include glycine, alanine, valine, leucine and isoleucine. This structure acts as recognition point for a sequence of modifications. First the terminal cysteine is farnesylated by farnesyl transferase, where a isoprenyl group is added to the cysteine residue -also called isoprenylation. This is followed by proteolytic cleavage of the aaX part by Zmpste24 and methylation (CH3) of cysteine. Isoprenylation and methylation are both necessary for the localization of lamin A and B-type lamins in to the INM. Until this point processing of lamin A and type-B lamins is similar. While in type-B lamins the isoprenyl group remains attached to the cysteine, lamin A has a second cleavage site to cleave off an additional 15 amino acids upstream of the cysteine. This cleavage is also done by Zmpste24 and takes place at INM. When these 15 amino acids, 18 in total including aaX, are cleaved off mature lamin A is produced (1,2). Lamin processing is involved in progeria.

Authors

Lora Simons , Denise Slenter , Egon Willighagen , Friederike Ehrhart , Laurent Winckers , and Eric Weitz

Activity

last edited

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Organisms

Homo sapiens

Communities

Rare Diseases

Annotations

Pathway Ontology

signaling pathway disease pathway

Disease Ontology

progeria disease

Participants
Query Drugst.One

Label Type Compact URI Comment
C Metabolite chebi:15356 Cysteine
15 amino acids Metabolite chebi:33709
C Metabolite chebi:15356
ZMPSTE24 GeneProduct ensembl:ENSG00000084073
LMNA GeneProduct ensembl:ENSG00000160789
Pre-lamin A GeneProduct uniprot:P02545
CAAX prenyl protease 1 homolog Protein uniprot:O75844
Protein-S-isoprenylcysteine O-methyltransferase Protein uniprot:O60725

References

  1. Nuclear lamins: laminopathies and their role in premature ageing. Broers JLV, Ramaekers FCS, Bonne G, Yaou RB, Hutchison CJ. Physiol Rev. 2006 Jul;86(3):967–1008. PubMed Europe PMC Scholia
  2. From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing. Cox LS, Faragher RGA. Cell Mol Life Sci. 2007 Oct;64(19–20):2620–41. PubMed Europe PMC Scholia