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Alpha/Beta Structures
Branden & Tooze, Chapter 4
Alpha / Beta Structures
• The most regular and common domain structures
consist of repeating beta-alpha-beta super-secondary
units
– A central core of parallel beta sheets surrounded by outer
layer of alpha helices. These folds are called alpha/beta, or
wound alpha beta.
• There are three main classes
of a/b proteins (built from b-a-b folds):
– TIM barrel
– Rossman Fold (open sheets)
– Horseshoe fold
TIM Barrel
Triosephosphate isomerase
• Triose-phosphate isomerase (TPI or
TIM) catalyzes isomerization of
dihydroxyacetone phosphate and Dglyceraldehyde 3-phosphate during
glycolysis.
•Structurally, TIM consists of a core of
twisted parallel b strands arranged
surrounded by a helices (sequential ba-b motifs).
•Function as a dimer (2 connected subunits).
•In humans, TPI deficiencies associated
with a progressive, severe neurological
disorder called triose phosphate
isomerase deficiency, characterized by
chronic hemolytic anemia. Usually
associated with mutation of E at position
104 to D.
Orosz, F.; Oláh, J. (2008). "Triosephosphate isomerase deficiency: facts and doubts". IUBMB Life 58 (12): 703–715
Properties of TIM Barrel
 a/b-barrel has been found
in more than 15 proteins.
 Most are enzymes with
completely different AA
sequences and functions.
 Branched hydrophobic
side chains form the core
within these proteins.
• In most a/b-barrel structures the eight b strands of the barrel
enclose a tightly packed hydrophobic core formed entirely
by side chains from the b strands. The core is arranged in
three layers, with each layer containing four side chains
from alternate b strands. The schematic diagram shows this
packing arrangement in the a/b barrel of the enzyme
glycolate oxidase.
Methylmalonyl-coenzyme A Mutase
• One exception, the inside
of the barrel
methylmalonyl-coenzyme A
mutase is lined by small
hydrophilic side chains
(serine and threonine) from
the b strands, which
creates a hole in the middle
where one of the substrate
molecules, coenzyme A
(green), binds along the
axis of the barrel from one
end to the other.
• Deficiency of this enzyme
can cause Methylmalonic
acidemia, which can lead
to encephalopathy and
death, if untreated.
a/b Barrel Active
Site
•
The active site in all a/b barrels is a
pocket formed by the flexible loop regions
that connect the carboxy ends of the b
strands with the adjacent a helices (a).
•
A view from the top of the barrel of the
active site of the enzyme RuBisCo
(ribulose bisphosphate carboxylase),
which is involved in CO2 fixation in plants
and requires binding of Mg2+ in the active
site.
Alpha / Beta Structures
Open a/b Sheet
•
•
•
Open twisted b-sheets are
surrounded by a-helices on
both sides of the b-sheets.
From the topology shown, a
loop-helix-loop sequence
creates a separation, or
crevice, between b-strands,
which is the active site.
2 examples of different types of
open twisted a/b structures (a)
the FMN(flavin
mononucleotide)-binding redox
protein Flavodoxin and (b) the
enzyme adenylate kinase,
which catalyzes the reaction
AMP + ATP ↔ 2 ADP.
Active Site of Open a/b Sheet
• There are always two adjacent bstrands on opposite sides of a bsheet. One of the loops from one
of these two b-strands goes
above the b-sheet, whereas the
other loop goes below, which
creates a crevice outside the
edge of the b-sheet between two
loops.
• Almost all binding sites in this
class of proteins are located in
crevices at the carboxy end of
the b sheet.
•A schematic view of the active site of tyrosyl-tRNA synthetase. Tyrosyl adenylate,
the product of the first reaction catalyzed by the enzyme, is bound to two loop
regions: residues 38 - 47, which form the loop after b strand 2, and residues 190 - 193,
which form the loop after b strand 5. The tyrosine and adenylate moieties are bound
on opposite sides of the b sheet outside the carboxy ends of b strands 2 and 5.
a/b–horseshoe
Fold
a/b –horseshoe Fold is formed by amino acid
sequences that contain repetitive regions of a
specific pattern of a helices and b-strands. The b
strands form a curved parallel b sheet with all the
a helices on the outside.
Schematic diagram of the structure of the
ribonuclease inhibitor. The molecule, which is built
up by repetitive b-loop-a motifs, resembles a
horseshoe with a 17-stranded parallel b sheet on
the inside and 16 a helices on the outside.
Leucine-rich Motifs
• Consensus amino acid sequence and
secondary structure of the leucine-rich
motifs of type A and type B. “X”
denotes any amino acid; “a” denotes
an aliphatic amino acid. Conserved
residues are shown in bold in type B.
• In the ribonuclease inhibitor, leucine
residues 2, 5, and 7 from the b strand
pack against leucine residues 17, 20,
and 24 from the a helix as well as
leucine residue 12 from the loop to
form a hydrophobic core between the
b strand and the a helix.
Alpha / Beta Structures
Visualization using Chimera
PDBfile 2fcr
•
“Crystal Structure of Oxidized Flavodoxin from a red algae Chondrus
crispus refined at 1.8A resolution. Description of the flavin mononucleotide
binding site.” Fukuyama, K. (1992) J. Mol. Biol. 225: 775-789. PubMed
1602481.
PDBfile 1fue
Flavodoxin from Helicobacter pylori. Freigang, J. 2002.
PDBfile 4h2d
NDOR1 (NADPH-dependent diflavin oxidoreductase 1. Banci, L.
2013.