Francesca Malagrinò

In the wisdom of Odin: modular architecture, receptor trafficking and therapeutic implications

Valeria Pennacchietti, Francesca Malagrinò, Stefano Gianni

Odin (ANKS1A) is a multidomain adaptor protein originally identified as a substrate of receptor tyrosine kinases. Over the past two decades, studies have revealed functions that extend beyond canonical growth factor signaling. At the molecular level, Odin participates in receptor signaling and …

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Determinants of Protein Folding Pathways: Lessons from Metamorphic Proteins

Valeria Pennacchietti, Mariana Di Felice, Julian Toso, Laura Caldarelli et autres

The protein folding problem has traditionally been defined by two complementary challenges: predicting the three-dimensional structure of a protein from its amino acid sequence and understanding the mechanism by which this structure is attained. While recent advances in artificial intelligence have largely …

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Conformational selection and linker-dependent specificity in the MAGI-1 WW tandem

Julian Toso, Eduarda Santos Ventura, Valeria Pennacchietti, Mariana Di Felice et autres

Scaffold proteins frequently employ tandem interaction domains to achieve affinity and specificity beyond that of individual modules. The MAGI-1 scaffold, a member of the membrane-associated guanylate kinase family, contains a central WW tandem whose mechanistic contribution to ligand recognition has remained unclear. …

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Adjacent domains drive the emergence of misfolded intermediates in the folding pathway of the PDZ4 from MAGI1

Valeria Pennacchietti, Cosmin Marian Obreja, Dimitrios Marinidis, Sara Di Matteo et autres

Protein misfolding in multidomain assemblies emerges from a complex interplay between intra- and interdomain interactions. Here, we dissect how neighboring domains shape the folding and misfolding of the PDZ4 domain from the scaffold protein MAGI1. Exploiting the single intrinsic tryptophan in PDZ4, …

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Unveiling an unexpected redox regulation of the folding, function and inhibition in the phosphotyrosine binding domain of FRS2

Valeria Pennacchietti, Livia Pagano, Mariana Di Felice, Julian Toso et autres

Protein-protein interaction domains are essential for cellular homeostasis and the regulation of various molecular pathways, mediating highly specific and reversible binding events. The PhosphoTyrosine-Binding domains (PTB) play a pivotal role in regulating several cellular events, by recognizing phosphorylated and, in some cases, …

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A PDZ tandem repeat folds and unfolds via different pathways

Valeria Pennacchietti, Sara Di Matteo, Livia Pagano, Fran Bačić Toplek et autres

Protein folding and unfolding experiments are interpreted under the assumption of microscopic reversibility, that is, that at equilibrium one process is the reverse of the other. Single-domain proteins illustrate the validity of such an interpretation, although reversibility does not necessarily hold under …

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GRB2: A dynamic adaptor protein orchestrating cellular signaling in health and disease

Francesca Malagrinò, Elena Puglisi, Livia Pagano, Carlo Travaglini‐Allocatelli et autres

GRB2, or Growth Factor Receptor-Bound Protein 2, is a pivotal adaptor protein in intracellular signal transduction pathways, particularly within receptor tyrosine kinase (RTK) signaling cascades. Its crystal structure reveals a modular architecture comprising a single Src homology 2 (SH2) domain flanked by …

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Folding and Binding Kinetics of the Tandem of SH2 Domains from SHP2

Livia Pagano, Valeria Pennacchietti, Francesca Malagrinò, Mariana Di Felice et autres

The SH2 domains of SHP2 play a crucial role in determining the function of the SHP2 protein. While the folding and binding properties of the isolated NSH2 and CSH2 domains have been extensively studied, there is limited information about the tandem SH2 …

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The Mechanism of Folding of Human Frataxin in Comparison to the Yeast Homologue – Broad Energy Barriers and the General Properties of the Transition State

Paola Pietrangeli, Lucia Marcocci, Valeria Pennacchietti, Awa Diop et autres

The funneled energy landscape theory suggests that the folding pathway of homologous proteins should converge at the late stages of folding. In this respect, proteins displaying a broad energy landscape for folding are particularly instructive, allowing inferring both the early, intermediate and …

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The binding selectivity of the C-terminal SH3 domain of Grb2, but not its folding pathway, is dictated by its contiguous SH2 domain

Mariana Di Felice, Livia Pagano, Valeria Pennacchietti, Awa Diop et autres

The adaptor protein Grb2, or growth factor receptor-bound protein 2, possesses a pivotal role in the transmission of fundamental molecular signals in the cell. Despite lacking enzymatic activity, Grb2 functions as a dynamic assembly platform, orchestrating intracellular signals through its modular structure. …

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Exploring the short linear motif-mediated protein-protein interactions of CrkL through ProP-PD

L. Pagano, Leandro Simonetti, Valeria Pennacchietti, Angelo Toto et autres

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Addressing the Binding Mechanism of the Meprin and TRAF-C Homology Domain of the Speckle-Type POZ Protein Using Protein Engineering

Awa Diop, Paola Pietrangeli, Valeria Pennacchietti, Livia Pagano et autres

Protein-protein interactions play crucial roles in a wide range of biological processes, including metabolic pathways, cell cycle progression, signal transduction, and the proteasomal system. For PPIs to fulfill their biological functions, they require the specific recognition of a multitude of interacting partners. …

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