Hepatocyte Nuclear Factor 1alpha

Maddy Anderson '22 and Callie Toal '22


Contents:


I. Introduction

Hepatic Nuclear Factors (HNFs) have 4 different structural classes based on their DNA binding domain, which are HNF1(alpha and beta), HNF3 (FOXA), HNF4, and HNF6. Hepatocyte nuclear factor 1alpha (HNF-1alpha) is our protein of interest. It is necessary for the expression of genes that influence the growth and development of beta cells in the pancreas, which secrete insulin and control blood glucose levels. This transcription factor is also needed to control the growth and development of liver cells, which play a role in the maintenance of homeostasis, numerous metabolic processes, and cell differentiation. HNF1 gene expression is generally only activated during organogenesis, when differentiation has reached a more advanced level.HNF-1alpha has three functional domains. 


II. General Structure

HNF-1alpha contains dimers and is of a structural weight of 57.86 kDa. This protein consists of 385 residues.It has 3 functional domains: an N-terminal domain, a DNA binding domain, and a carboxyl-terminal domain. The is responsible for dimerization and the carboxyl-terminal domain is responsible for transactivation (The carboxyl-terminal domain has not yet been crystallized and isolated). A flexible linker connects the DNA binding domain to the dimerization domain. The DNA binding domain contains 2 POU-homeodomains. There is also a dimerization cofactor for HNF1-alpha that binds to the amino-terminal domain, stabilizing the dimers. 


III. Dimerization

The dimerization region consists of residues 1-32. The dimer is symmetrical with cyclic C-2 symmetry and a single 2-fold axis.The dimerization is a bundle of These helices make up what researchers describe as a rigid and a flexible element.

The rigid element is like a mini zipper that contains the alpha helices 1 and 1’. Alpha helix 1 is involved in a Schellman motif and is capped off by glycine 20 in the wild type. Here researchers have subsituted G20 with for greater stability. The flexible element contains alpha helices 2 and 2’ whose C-terminals are oriented in a variety of ways. The two elements are connected by a non-canonical tight turn.

The includes an H-bond between L21 and L16, an H-bond between G20 and L17, and nonpolar interactions between L21 and L16 side chains. There is also a pattern of H-bonding in the main chain accompanied by a water-bridge network, which also mediates 3 H-bonds between G20 and L21.


IV. DNA Binding

The bipartite DNA-binding motif contains a variant POU-homeodomain and a more constant POU-homeodomain. The more divergent homeodomain consists of 3 alpha helices which contain variation due to insertions. This domain uses the The more specific POU-homeodomain contains

The two POU-homeodomains are linked by residues 182-200 to form a dimer, but this linkage is disordered. Both of these POU-homeodomains bind the same face of the DNA. The DNA binding region recognizes palindromic sequences in the DNA. The involved in binding to the DNA through H-bonds are R272, Y218, R271, R263, R203, T260, R229, K205, P129, R131, S142, H143, H147, R159, and K158.  


V. Activating Regions

The activating region of HNF-1alpha is found in the carboxyl-terminal domain. The C-terminal region of HNF-1 is responsible for the activation of transcription and is thought to interact with both the DNA-binding homeodomains as well as other transcription factors.. This region of the protein is extremely variable and contains residues 281-631. We were unable to locate a PDB of HNF-1alpha that included this region. The exact mechanisms of activation performed by HNF-1alpha still remain unclear.



VI. References

Chi, Y., Frantz, J. D., Oh, B., Hansen, L., Dhe-Paganon, S., Shoelson, S. E. (2002). Diabetes Mutations Delineate an Atypical POU Domain in HNF-1?. Molecular Cell,10(5), 1129-1137. doi:10.1016/S1097-2765(02)00704-9

Lau, H. H., Ng, N. H., Loo, L. S., Jasmen, J. B., & Teo, A. K. (2018). The molecular functions of hepatocyte nuclear factors – In and beyond the liver.Journal of Hepatology,68 (5), 1033-1048. doi:10.1016/j.jhep.2017.11.026.

Narayana, N., Phillips, N. B., Hua, Q., Jia, W., & Weiss, M. A. (2006). Diabetes Mellitus due to Misfolding of a ?-Cell Transcription Factor: Stereospecific Frustration of a Schellman Motif in HNF-1?. Journal of Molecular Biology,362(3), 414-429. doi:10.1016/j.jmb.2006.06.086

Wang, X., Hassan, W., Zhao, J., Bakht, S., Nie, Y., Wang, Y., . . . Huang, Z. (2019). The impact of hepatocyte nuclear factor-1? on liver malignancies and cell stemness with metabolic consequences Stem Cell Research & Therapy,10. doi:10.1186/s13287-019-1438-z

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