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Helix-loop-Helix Motif:
Simple is Not Boring!
Chet Fornari, Jennifer Inlow,
Larry Merkle, Barry Muhoberac,
Yosi Shibberu
From http://www.biologie.uni-hamburg.de/lehre/mikro/mikro402/mi4_711i.jpg
The beauty, simplicity, and elegance of the
helix-loop-helix protein structural motif makes it
an excellent instructional tool.
(A) The carboxyl-terminal helix (red) is called the recognition helix because it
participates in sequence-specific recognition of DNA.
(B) This helix fits into the major groove of DNA, where it contacts the edges
of the base pairs.
From Molecular Biology of the Cell. 3rd ed. Alberts, Bruce; Bray, Dennis; Lewis, Julian; Raff, Martin;
Roberts, Keith; Watson, James D. New York and London: Garland Publishing; c1994.
Detail of interactions between recognition helix and DNA
Homeodomain-DNA Complex
A common, fundamental structural motif of diverse proteins
that interaction with DNA, such as transcription factors,
restriction enzymes, and topoisomerases:
Examples:
bacteria
yeast
drosophila
mammals
Two aspects to this problem space
Structure
and
Binding
Evolutionary
Aspects
Structure and Binding
1. Structure
identify stabilizing and targeting helices
helical wheels, amphipathicity
surface charge calculations
2. Binding
generalized charge effects in approach
geometric constraints
specific charge-charge or hydrogen-bonding interactions
ligand docking simulation enhanced with 3-D
visualization and haptics
Example of a student exercise:
transcription regulator protein containing helix-loop-helix
motif from Methanococcus maripaludis
Interactive java helical wheel
http://marqusee9.berkeley.edu/kael/helical.htm
Evolutionary Aspects
1. Evolution over taxa of a particular HtH domain-containing
protein
tools: CLUSTALW, Phylip
2. Evolutionary utilization of this motif by different enzymes
tools: BLAST, CLUSTALW, Domain search
different sequence = same structure ?
Tree for homeodomain engrailed from diverse
organisms as analyzed through NCBI and Workbench
BLASTP Homology search for Human “Engrailed Homolog 1”
Homologous to mouse, chicken, rat, zebra fish, worm
Human Engrailed Homolog 1
Conserved protein domain search
using NCBI CD-Search