36 research outputs found
DataSheet1_A computational study of the structure and function of human Zrt and Irt-like proteins metal transporters: An elevator-type transport mechanism predicted by AlphaFold2.docx
The ZIP (Zrt and Irt-like proteins) protein family includes transporters responsible for the translocation of zinc and other transition metals, such as iron and cadmium, between the extracellular space (or the lumen of organelles) and the cytoplasm. This protein family is present at all the phylogenetic levels, including bacteria, fungi, plants, insects, and mammals. ZIP proteins are responsible for the homeostasis of metals essential for the cell physiology. The human ZIP family consists of fourteen members (hZIP1-hZIP14), divided into four subfamilies: LIV-1, containing nine hZIPs, the subfamily I, with only one member, the subfamily II, which includes three members and the subfamily gufA, which has only one member. Apart from the extracellular domain, typical of the LIV-1 subfamily, the highly conserved transmembrane domain, containing the binuclear metal center (BMC), and the histidine-rich intracellular loop are the common features characterizing the ZIP family. Here is presented a computational study of the structure and function of human ZIP family members. Multiple sequence alignment and structural models were obtained for the 14 hZIP members. Moreover, a full-length three-dimensional model of the hZIP4-homodimer complex was also produced. Different conformations of the representative hZIP transporters were obtained through a modified version of the AlphaFold2 algorithm. The inward and outward-facing conformations obtained suggest that the hZIP proteins function with an “elevator-type” mechanism.</p
Video1_A computational study of the structure and function of human Zrt and Irt-like proteins metal transporters: An elevator-type transport mechanism predicted by AlphaFold2.MP4
The ZIP (Zrt and Irt-like proteins) protein family includes transporters responsible for the translocation of zinc and other transition metals, such as iron and cadmium, between the extracellular space (or the lumen of organelles) and the cytoplasm. This protein family is present at all the phylogenetic levels, including bacteria, fungi, plants, insects, and mammals. ZIP proteins are responsible for the homeostasis of metals essential for the cell physiology. The human ZIP family consists of fourteen members (hZIP1-hZIP14), divided into four subfamilies: LIV-1, containing nine hZIPs, the subfamily I, with only one member, the subfamily II, which includes three members and the subfamily gufA, which has only one member. Apart from the extracellular domain, typical of the LIV-1 subfamily, the highly conserved transmembrane domain, containing the binuclear metal center (BMC), and the histidine-rich intracellular loop are the common features characterizing the ZIP family. Here is presented a computational study of the structure and function of human ZIP family members. Multiple sequence alignment and structural models were obtained for the 14 hZIP members. Moreover, a full-length three-dimensional model of the hZIP4-homodimer complex was also produced. Different conformations of the representative hZIP transporters were obtained through a modified version of the AlphaFold2 algorithm. The inward and outward-facing conformations obtained suggest that the hZIP proteins function with an “elevator-type” mechanism.</p
Average values of the structure-related parameters.
1<p>evaluated by Wilcoxon test.</p>2<p>evaluated by Fligner-Killeen test.</p><p>Average values of the structure-related parameters were calculated for natural proteins and random ones. Both mean and variance were significantly different for all variables with a test significance level of 0.01 except for variables Coil, % Coil and surface area.</p
Scatter plot of the structural properties.
<p>Overlap of the scatterplots for the two classes of proteins for each variable pairs. Random proteins are represented in green, Natural ones are represented in red.</p
Superimposition of model A00084 and 2ZYZ.
<p>Schematic representation of the superposition of model A00084 (orange) and the <i>Pyrobaculum aerophilum</i> splicing endonuclease (light blue) (PDB code 2ZYZ chain A). a) front view, b) top view.</p
Superimposition of model A00927 and 1UUG.
<p>Schematic representation of the superposition of model A00927 (light blue) and the uracil-DNA glycosylase inhibitor protein (red) (PDB code 1UUG chain B). a) Front view, b) back view.</p
Overview of the structural analysis of classified random proteins.
<p>Fold recognition of classified and misclassified random proteins. Both mean and variance were significantly different for Z-score and RMSD variables with a test significance level of 0.01.</p
A comprehensive <i>in silico</i> analysis of huntingtin and its interactome
<p>A polyglutamine expansion of the <i>N</i>-terminal region of huntingtin (Htt) causes Huntington’s disease, a severe neurodegenerative disorder. Htt huge multidomain structure, the presence of disordered regions, and the lack of sequence homologs of known structure, so far prevented structural studies of Htt, making the study of its structure-function relationships very difficult. In this work, the presence and location of five Htt ordered domains (named from Hunt1 to Hunt5) has been detected and the structure of these domains has been predicted for the first time using a combined threading/<i>ab initio</i> modeling approach. This work has led to the identification of a previously undetected HEAT repeats region in the Hunt3 domain. Furthermore, a putative function has been assigned to four out of the five domains. Hunt1 and Hunt5, displaying structural similarity with the regulatory subunit A of protein phosphatase 2A, are predicted to play a role in regulating the phosphorylation status of cellular proteins. Hunt2 and Hunt3 are predicted to be homologs of two yeast importins and to mediate vescicles transport and protein trafficking. Finally, a comprehensive analysis of the Htt interactome has been carried out and is discussed to provide a global picture of the Htt’s structure–function relationships.</p
Descriptive statistics of the structural properties of random and natural proteins.
<p>Descriptive comparison of natural and random proteins by means of: boxplot of the variables distribution in the two classes (top) and histogram of the variables distribution with the corresponding Kernel density estimate (bottom).</p
Descriptive statistics of the structural properties of random and natural proteins.
<p>Descriptive comparison of natural and random proteins by means of: boxplot of the variables distribution in the two classes (top) and histogram of the variables distribution with the corresponding Kernel density estimate (bottom).</p