18 Flashcards
progeria is a type of —?
laminopathy
What is the major player that cells use to kill invading bacteria?
Neutrophils and NETs (Netosis)
What is PAD4 and what proteins does it act on?
PAD4 (enzyme) primarily acts on histones, particularly in the context of chromatin remodeling.
- unpacks heterochromatin
Progeria cause/mutation?
In HGPS, a mutation in the LMNA gene creates an abnormal form of Lamin A called Progerin.
Progerin retains the toxic farnesyl and methyl groups because the final cleavage step by ZMPSTE24 cannot occur.
Farnesylation of Pre-Lamin A
Farnesylation is the attachment of a farnesyl group (a lipid) to a cysteine residue in the CaaX motif at the C-terminus of pre-Lamin A.
what is the Caax?
The CaaX motif consists of:
C = Cysteine (where farnesyl is attached)
aa = Two aliphatic amino acids
X = Any amino acid (determines enzyme specificity)
the cite that is targeted for cleavge in pro-lamin A
Processing of Pre-Lamin A
After farnesylation, the CaaX motif is cleaved by the enzyme ZMPSTE24 (or RCE1), removing the last three amino acids (aaX).
Then, the newly exposed cysteine is methylated by ICMT
Normally, ZMPSTE24 also cleaves the C-terminus again, removing the farnesylated and methylated region to produce mature Lamin A.
What is RCE1?
RCE1 (Ras Converting Enzyme 1) is an endoprotease (enzyme that cleaves proteins) found in membranes.
It is crucial for processing proteins that undergo prenylation (attachment of lipid groups like farnesyl or geranylgeranyl).
RCE1 Role in Protein Processing
After a protein like Ras or pre-Lamin A gets prenylated (farnesylated or geranylgeranylated), RCE1 removes the last three amino acids (CaaX motif).
This step is essential for proper localization of these proteins to membranes.
Why are RCE1 Mutations Lethal?
Since Ras mislocalization can contribute to cancer and developmental disorders, the enzyme’s function is tightly regulated.
What do Lamins Contribute?
- Genome organization and chromatin structure
- Transcriptional regulation
- Link b/n nucleus & cytoplasm via cytoskeletal elements (i.e., positioning)
- Provides a platform for cell-signaling complexes
So what does Progeria (HGPS) do?
Progerin may contribute to normal aging
Progerin in normal cells causes abnormalities seen in HGPS
HGPS & naturally aged cells have reduced nucleosome remodeling deacetylase (NuRD)
chromatin modifying complex
Reducing NuRD complex constituents cause ?
HGPS
Role of NuRDs?
Nucleosome Remodeling and Deacetylase complexes) are protein complexes that help regulate gene expression by:
1) Remodeling chromatin (moving or changing the structure of nucleosomes)
2) Deacetylating histones (removing acetyl groups to tighten DNA packing)
Where are Lamins (A&C&B) found?
Inner Nuclear Membrane
What superfamily is Ran in?
Ras superfamily
