Biomedical subjects

Luca Pellegrini

Publications and source records attributed to Luca Pellegrini.

22 records · Page 2Linked to original sources

PubMed2003

Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2.

Here, we visualize GFP-Rad51 fusion proteins in the nucleus of living cells to demonstrate the dynamic compartmentalization of Rad51 by self-association or by binding to BRCA2. Mutants of Rad51 that fail to oligomerize and/or to bind BRCA2 distinguish three fractions of Rad51 within the nucleoplasm: a relatively mobile fraction, an immobile oligomerized fraction, and an immobile BRCA2-bound fraction. Strikingly, inhibition of replication by hydroxyurea reduces the immobile fraction of nucleoplasmic Rad51. This effect is specific to Rad51 mutants that retain the capacity to bind BRCA2, indicating that the BRCA2-bound fraction is selectively mobilized. We propose that arrested replication triggers a switch between dual functions of BRCA2 in sequestering or mobilizing a small fraction of nucleoplasmic Rad51 and suggest a mechanism for the dynamic control of protein complexes that participate in homologous recombination.

Animals↗

PubMed2002

Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.

The breast cancer susceptibility protein BRCA2 controls the function of RAD51, a recombinase enzyme, in pathways for DNA repair by homologous recombination. We report here the structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionary origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. Cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility.

Amino Acid Motifs↗

PubMed2002

Neuronal apoptosis is accompanied by amyloid beta-protein accumulation in the endoplasmic reticulum.

A series of evidences suggests that enhanced susceptibility to programmed cell death (PCD) is a major pathogenetic factor in Alzheimer's disease (AD). We investigated this issue, analyzing amyloid beta-protein (A beta) production in a model of neuronal PCD, induced by staurosporine in a murine neuroblastoma cell line. When PCD was induced, a 280-290% secreted A beta occurred, in spite of a 20% metabolism and an unchanged A betaPP expression. The increased intracellular A beta reactivity largely colocalized with a marker of ER. Inhibition of caspases blocked the cleavage at the C-terminus of beta PP, but only partially rescued A beta overproduction caused by staurosporine treatment. Our findings suggest that PCD fosters the physiological pathways of A beta production characteristic of neuronal cells, and they confirm the theory that unbalance of PCD is a central event in AD pathogenesis. Moreover, our data indicate that still unidentified cellular mechanisms, other than caspases activation, are responsible of the specific alteration of A betaPP processing during PCD.

Amyloid beta-Peptides↗

PubMed2001

PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2.

The familial Alzheimer's disease gene products, presenilin-1 and presenilin-2 (PS1 and PS2), are involved in amyloid beta-protein precursor processing (AbetaPP), Notch receptor signaling, and programmed cell death. However, the molecular mechanisms by which presenilins regulate these processes remain unknown. Clues about the function of a protein can be obtained by seeing whether it interacts with another protein of known function. Using the yeast two-hybrid system, we identified two proteins that interact and colocalize with the presenilins. One of these newly detected presenilin-interacting proteins belongs to the FtsH family of ATP-dependent proteases, and the other one belongs to Rhomboid superfamily of membrane proteins that are highly conserved in eukaryotes, archaea and bacteria. Based on the pattern of amino acid residues conservation in the Rhomboid superfamily, we hypothesize that these proteins possess a metal-dependent enzymatic, possibly protease activity. The two putative proteases interacting with presenilins could mediate specific proteolysis of membrane proteins and contribute to the network of interactions in which presenilins are involved.

Journal Article↗