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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