262,301 research outputs found
Recensione A. Tortoriello, "I Fasti consolari degli anni di Claudio"
No full textSi tratta della recensione al volume di Annalisa Tortoriello, pubblicato nel 2004 dall'Accademia Nazionale dei Lincei, nel quale si studiano i Fasti Consolari degli anni dell' Imperatore Claudio, quale elemento 'oggettivo' di particolare rilievo per la comprensione dei delicati e mutevoli rapporti tra princeps e Senato
CRBPs: different mechanisms of ligand entry in spite of high structural similarity.
No full textFour Cellular Retinol-Binding Protein (CRBP) isoforms, belonging to the intracellular lipid-binding protein (iLBP) family, have been reported in humans. Despite their low sequence identity they show a high structural conservation. CRBP 1 and 2, for which retinol is the endogenous ligand, bind it with high affinity, while CRBP3 and 4, for which the endogenous ligand is not yet characterized, show a very low affinity for retinol. One of the main differences concerning the binding site of the four isoforms is that the glutamine 108, one of the two key residues, is presents in CRBP1 and 2 while is replaced by a histidine in CRBP3 and 4. Our recent work about the characterization of the role of the key binding residues1, together with other previous studies, demonstrated that other unidentified factors, distinct from this substitution, are responsible of affinity differences between CRBPs. The different flexibility of the four isoforms could be an important feature to clarify this. To this aim, we have performed MD simulations of apo-proteins, observing different mobility in selected regions of the four proteins, in spite of their high structural conservation. Moreover, to understand the retinol up-take mechanism of the CRBP I and II, we have carried out MD simulations in the presence of the ligand. Our data suggest a different entry path for the retinol in CRBP1 and 2, even if involving the same “portal” region. We are performing the experimental characterization of mutant forms of the two CRBPs to validate the computational model.
1. Menozzi I, Vallese F, Polverini E, Folli C, Berni R, Zanotti G. Structural and molecular determinants affecting the interaction of retinol with human CRBP1. J Struct Biol. 2017;197(3). doi:10.1016/j.jsb.2016.12.012
Recensione di: Marziano Capella, "Le nozze di filologia e Mercurio" a cura di I. Ramelli.
No full textSi tratta di una attenta recensione del volume col testo dello scrittore pagano della tarda antichità Marziano Capella "Le nozze di Filologia e Mercurio" curato con ampia introduzione, traduzione, commento e approfondito apparato critico da Ilaria Ramelli.L'opera da tempo non era più disponibile sul mercato editoriale italiano dei classici con testo originale a fronte
Firmum Picenum I. A cura di Leandro Polverini, Nicola F. Parise, Silvano Agostini e Marinella Pasquinucci. Introduzione di Emilio Gabba
No full textPoucet Jacques. Firmum Picenum I. A cura di Leandro Polverini, Nicola F. Parise, Silvano Agostini e Marinella Pasquinucci. Introduzione di Emilio Gabba. In: L'antiquité classique, Tome 59, 1990. p. 606
Firmum Picenum I. A cura di Leandro Polverini, Nicola F. Parise, Silvano Agostini e Marinella Pasquinucci. Introduzione di Emilio Gabba
No full textPoucet Jacques. Firmum Picenum I. A cura di Leandro Polverini, Nicola F. Parise, Silvano Agostini e Marinella Pasquinucci. Introduzione di Emilio Gabba. In: L'antiquité classique, Tome 59, 1990. p. 606
Recensione di G.Cruz Andreotti, P.Le Roux y P.Moret (a cura di) La invencion de una geografia de la Peninsula Iberica, I (La época republicana), II (La época imperial)
No full textLa rassegna degli atti di due recenti convegni permette di rilevare, e discutere, alcuni aspetti metodologicamente significativi dell’attuale, caratteristico interesse per la geografia storica del mondo antico
Inside the mechanism of SMN-SmD1 protein complex formation: effects of the Spinal Muscular Atrophy - causing E134K mutation. A molecular dynamics simulation study.
No full textSpinal muscular atrophy (SMA) is a motor neuron disease that leads to muscle atrophy due to motor neurons degeneration. SMA is a major genetic cause of early childhood mortality and results from mutations in the Survival of Motor Neuron (SMN) gene1. The SMN protein plays a crucial role in the assembly of spliceosomal small nuclear ribonucleoprotein complexes via binding to the spliceosomal Sm core proteins, in particular to their arginine-glycine (RG) rich C-terminal tails. SMN contains a central Tudor domain, directly involved in the SMN–Sm protein interaction by the recognition of symmetrically dimethylated arginine (DMR) residues in the RG repeats. In particular, an aromatic cage on Tudor domain seems to mediate this binding (1–3).
Six of the pathogenic mutations causing SMA occur in the SMN Tudor domain. The only one that prevents the binding to the Sm proteins without a perturbation of the domain fold is E134K, that is the cause of the more severe type I SMA (3).
To gain more understanding about the mechanism by which SMN interacts with the Sm proteins, and which are the structural effects on binding of its deleterious mutation E134K, we investigated the behavior of the native and mutated structure of the SMN Tudor domain in the presence of the C-terminal tail of SmD1, by means of molecular dynamics simulations.
The interaction of the SmD1 tail with the Tudor domain is electrostatic driven by the acidic residues near the entrance of the aromatic cage. A central DMR of the tail enters into the cage rapidly and stably, forming a network of cationic-pi interactions, both in stacking and T-shaped. The complex is stabilized also by the salt-bridges formed by the other DMRs and arginine residues wrapped around the acidic surface of the domain.
The E134K mutation destabilizes the cage, not only with the disruption of the strong 134-136-127 H-bonds network, but also with the formation of new electrostatic and cationic-pi interactions. The cage collapses and expands, preventing a stable binding of the DMR. This is impeded also by the detachment of the C-terminal region of the tail from the Tudor domain, caused by the E134K charge inversion.
The results are in agreement with what experimentally observed (1–3) and clarify the key role of E134 in the interaction of the SmD1 tail to the Tudor domain. The loss of a strong Tudor-SmD1 interaction, if by one side causes the loss of a functional splicing machinery, by the other side causes the exposition of the detached Sm tails, that could stimulate the recognition by anti-Sm autoantibodies, as is reported for other diseases as lupus erithematosus (4), giving rise to the innovative hypothesis of SMA as an autoimmune disease.
1. P. Selenko et al., Nat. Struct. Biol. 8, 27–31 (2001).
2. R. Sprangers et al., J. Mol. Biol. 327, 507–520 (2003).
3. K. Tripsianes et al., Nat. Struct. Mol. Biol. 18, 1414–20 (2011).
4. H. Brahms et al., J. Biol. Chem. 275, 17122–17129 (2000)
A Step-based framework to combine creativity, project management, and technical development in industrial innovation
No full textHigh structural and functional conservation but different ligand uptake: the role of the hydropathy profile of the protein surface.
No full textCellular Retinol-binding Proteins (CRBP) type I and II are beta-barrel proteins that show very high structural conservation in spite of a moderately low sequence identity and a different tissue distribution. These retinol carriers play role in the maintenance of vitamin A homeostasis, but exhibit a different affinity for the ligand (100 folds higher for CRBP-I). However, the binding site of the two isoforms is highly conserved.
The mechanism of ligand uptake was investigated by means of molecular dynamics simulations, initially positioning the ligand outside the protein. For both CRBPs, the portal region formed by alfa helix II and the two loops between CD and EF strands is involved in the uptake, with a partial unfolding of the helix II. Nevertheless, a different distribution of polar and hydrophobic residues clusters at the surface of the two proteins, in particular at the barrel lid made by helix I and II, favored two different entrance pathways. In CRBP I, the retinol enters the binding cavity through a hydrophobic passage between alpha helix II and CD and EF loops, while in CRBP II the ligand, driven by a few polar interactions, sinks in the hydrophobic region between the two alpha helices. Then, in both cases, several polar residues interacting with OH-group, attract the retinol deeply inside the binding cavity. Therefore, even if the retinol uptake involves the same region, that covers the binding pocket and is intrinsically flexible, the ligand finds the better entrance pathway according to the hydropathy features of the protein surface
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