BioCAT is a mature user facility that supports several types of experiments.
One measure of the facility’s scientific impact is the number and quality of the
publications produced. As of August 2019, the Web of Science
shows that the facility and its users had published more than 500 articles, which had
been cited more than 20000 times with an average number of citations per article
The APS provides a list of all BioCAT publications
When you publish your science from BioCAT, please follow
Below is a gallery of a few of BioCAT’s science highlights.
Tarantula myosin interacting-heads motif explains tetanic and post-tetanic phosphorylation mechanisms
Striated muscle contraction involves sliding of actin thin filaments along
myosin thick filaments, controlled by calcium through thin filament
activation. In relaxed muscle, the two heads of myosin interact with each
other on the filament surface to form the interacting-heads motif (IHM).
A key question is how both heads are released from the surface to approach
actin and produce force. We used time-resolved synchrotron X-ray diffraction
to study tarantula muscle before and after tetani. The patterns showed that
the IHM is present in live relaxed muscle.
Nebulin mutations causing nemaline myopathy in humans change the structure of thin filaments in muscle
Nebulin is a giant protein that winds around the actin filaments in the
sarcomeres of skeletal muscle. Mutations in the nebulin gene (NEB) cause
typical nemaline myopathy (NM), a muscle disorder characterized by muscle
weakness that are difficult to treat. The authors of this study
created a mouse model that mimics the typical nebulin-based NM patient
with compound-heterozygous mutations. X-ray diffraction studies on the
BioCAT beamline 18ID provided a structural explanation for the muscle
weakness. This new Compound-Het mouse model will be useful for testing
experimental therapies for typical NM.
Structure-Function Studies Elucidate GPCR-Independent Regulation of G-proteins
Guanine nucleotide binding proteins popularly known as G-proteins,
involved in a variety of cellular signal transduction pathways are
heterotrimeric proteins consisting of α, β, and γ subunits. Ric8A is
known to be both a chaperone for the assembly of the α-subunit of G-proteins,
and a Guanine nucleotide Exchange Factor (GEF). McClelland et al., have
conducted a detailed structural analysis on the complex between Ric8A
and Gαi1 using cryoEM, X-ray crystallography, and SAXS.
How Prion-like domains Drive Liquid-Liquid Phase Transitions in Cells
Liquid-liquid phase separation (LLPS) provides a way for
cells to create membraneless micro-environments (“condensates”)
that have been proposed to be involved in diverse cellular
processes including stress responses, RNA splicing, mitosis,
chromatin organization, and the clustering of receptors at
membranes. Proteins driving LLPS often contain intrinsically
disordered prion like domains (PLD’s) that appear to be
necessary and sufficient to produce LLPS. In a recent paper
in the journal Science, researchers used a combination of NMR,
multiscale simulations and Size Exclusion Chromatography SAXS
experiments at BioCAT to discover sequence features that determine
the phase behavior of PLD’s.
Sarcomere Structure and Nemaline Myopathy
Nemaline myopathy (NM) is one of the most common congenital non-dystrophic
myopathies and is characterized by severe hypotonia, muscle weakness,
feeding difficulties, respiratory failure, and the presence of nemaline
bodies (rods) in skeletal muscle biopsies. One form of nemaline myopathy
is caused by mutations in the KBTBD13 (NEM6) gene. A combination of
transcranial magnetic stimulation-induced muscle relaxation, muscle fiber-
and sarcomere-contractility assays, super-resolution microscopy, and low
angle X-ray diffraction at BioCAT revealed that the
impaired muscle relaxation kinetics in NEM6 patients are caused by
structural changes in the thin filament, a sarcomeric microstructure.
Structure-Function Understanding of aGPCR ECRs Critical for Drug-Design
Cellular communication mediated by a variety of cell-surface receptors
involves ligand induced conformational changes in the extracellular
region (ECR). A variety of drugs such as cetuximab (Epidermal Growth
Factor Receptor), etrolizumab (Integrins), and erenumab (calcitonin
receptor-like receptor) function by trapping ECRs in specific conformations
and have proved to be effective therapeutic agents in several cancers,
bowel diseases, and migraine. Leon et al., studied a class of
relatively understudied G-protein couple receptors (GPCRs) called
adhesion-GPCRs (aGPCRs) which have a structurally unique ECR with a
diverse set of mechanistic possibilities.
Cold temperatures put myosin in a refractory state unable to bind to actin
The myosin heads in relaxed muscle are in an ordered
quasi-helical arrangement around the thick filament backbone where they
are unable to bind to actin. Current models propose that strain developed
in the thick filament backbone generated by a small number of disordered,
constitutively active myosin heads, once the strain surpasses some threshold,
releases myosin heads form the ordered inactive heads to become disordered
active heads. At this point, it is commonly assumed that ordered heads are
in the OFF state, unable to bind to actin, while disordered heads are in
the ON state, able to bind to actin and generate force. In a recent paper
in J. General Physiology, researchers from the University Florence used
the BioCAT Beamline 18ID to show that this is not necessarily always true,
at least in mouse skeletal muscle.
Frustration and Folding of a TIM Barrel Protein
In their continuing endeavor to understand misfolding proteins as part of
the etiology of a variety of diseases, the Matthews lab particularly focuses
on the different factors that impede a protein’s path from the unfolded state
to the global free energy minimum. The complexity of the folding trajectory
understandably depends on the size of the protein mostly because of the
formation of intermediates many of which often stall the formation of an
optimal native conformation.
Structure of BS Ric8A, a regulator of G-protein Biology
Ric8A is a well-known
regulator of G-protein biology and belongs to a class of proteins different
from the G protein-coupled receptors (GPCRs), which act via interactions
with monomeric Gα subunits as opposed to heterotrimeric Gαβγ proteins.
SAXS was used in combination with crystallography and biochemical studies
to show that the flexible C-terminal tail is important for the overall
stability of Ric8A and the function as a guanine nucleotide exchange
Probing the Powering of Contractions in Heart Failure
Current treatments can slow progression of heart failure,
but do not address the underlying issues, including specific
problems that cause systolic heart failure. In this condition,
the heart doesn’t contract vigorously enough in pushing blood
into the body’s circulation. But findings at nanometer and
millisecond scales, based upon experimental data collected at
BioCAT may help improve design of therapies directed at motor
proteins to rescue failing hearts.
New Insights into Traumatic Brain Injury
Traumatic brain injury, or TBI, is often referred to as the “invisible
injury” — while on the surface everything seems normal with brain structure,
symptoms may present themselves in the behavior of the injured and cannot
be explained. This work looked at the effect of controlled
amounts of compressive force on rat optic nerves to attempt to identify
the changes that occur in otherwise normal looking brain neurons due to
the specific impact forces experienced during head trauma. As a result
of this ongoing work, researchers have a better understanding
of what kind of experience, or injury, leads to what kind of damage in the
myelin - helping to visualize injuries based on the smallest force
necessary to cause it. This information may be critical to knowing when
someone has an injury after an accident but before symptoms emerge, and
help supports the decision of when and how to treat them.
Mechanistic Insights into Insulin Degrading Enzyme from Laminar-Flow SAXS
Insulin Degrading Enzyme (IDE) is known known to be a significant
factor in the pathophysiology of conditions such as Diabetes
mellitus and Alzheimer’s disease. This paper reveals structural
states present during substrate recognition and capture and
identifies a potential rate limiting step in the reaction.
A Target Mutation that Renders a Cancer Drug Ineffective
Mutations in the gene PTPN11, which encodes a common enzyme
called SHP2, can result in developmental disorders, such as
Noonan Syndrome, and act as oncogenic drivers in patients with
certain blood cancers. Due to the well understood role of the
enzyme SHP2 in Noonan Syndrome and in tumorigenesis, many
companies are currently trying to develop drugs that inhibit
the enzyme. Researched investigated what impact mutations to
SHP2 may have on the potential efficacy of drugs targeting
A Super-relaxed Myosin State to Offset Hypertrophic Cardiomyopathy
Researchers investigated the stabilizing action of mavacamten,
a cardiac drug currently in phase 3 clinical trials, on the
ß-cardiac myosin super-relaxed state and its possible therapeutic
effects on hypertrophic cardiomyopathy.
Unraveling the role of a “nebulous” protein
Nebulin is a protein important to muscle strength, as
mutations can cause the muscles in patients with nemaline
myopathy disease to be weak, little is known about how it
works. Researchers investigated the function of Nebulin in
mice and found that it is necessary for generating physiological
levels of force.
Proteins May Prevent Dysfunction and Disease by Relaxing
A new study suggests many proteins remain expanded in the cell,
rather than contracting into tight folded shapes.
Unearthing the Mechanism of the Frank-Starling Law
Recent X-ray diffraction experiments show that the protein
titin is critically important for transmitting the stretch-induced
signals within the heart’s muscles known to impact the strength with
which the heart contracts. This work not only solves a piece of the
mystery of how the frank-Starling law determines cardiac function, but
provides an avenue for targeted development of drugs to treat heart failure.
TAPBR: A Novel Protein Chaperone With a Role in Peptide Editing in Immune Recognition
TAP binding protein, related (TAPbPr), a novel protein
chaperone, plays a role in loading peptides onto major
histocompatibility class i (mhc i) molecules during the
process of immune surveillance. Researchers investigated
the biochemical function of TAPbPr, comparing it with
tapasin, another chaperone with a similar protein sequence.
The results of this study could lead to ways to modulate
peptide loading in vaccine design, improving T-cell recognition.
Combating an Infectious Invader
The investigation of the fungal prion HET-s(218-289) provides
insights into the fundamental mechanisms of prion assembly and
propagation of its infectious fold, which is made robust by a
complex and diverse array of inter and intramolecular structural
features. This level of complexity has not been observed in
short-peptide amyloids that have been used as prion model systems.
The cross-bridge spring: cool muscles store elastic energy
The Hawkmoth Manduca sexta is an emerging model system for a
wide range of studies in integrative biology. The flight muscles
are particularly interesting in that, unlike most insect flight
muscle, but like vertebrate skeletal and cardiac muscles, they
are a synchronous muscle where each stimulus generates one muscle twitch.
The Molecular Mechanism of Stretch Activation in Insect Muscle
Flying insects are among the most successful species on our
planet. Flight is very metabolically demanding and many insects
have found a clever way to reduce energy costs in their flight
muscles by employing a process called “stretch activation, which
has been recognized since the 1960s as an interesting and
physiologically important phenomenon, but a mechanistic explanation
has been elusive. Now, research at BioCAT provides another,
important step toward a full explanation of stretch activation,
which also plays an important role in mammalian cardiac
expansion and contraction.
Packing It In: A New Look at Collagen Fibers
Nature uses collagen everywhere in constructing multicellular
animals. There are at least 20 types of collagen, but 80-90% of
the collagen in the body consists of types I, II, and III.
Collagen type II makes up 50% of all cartilage protein, and
is essential in normal formation of such structures as
cartilage, the vitreous humor of the eye (the clear gel
that fills the space between the lens and the retina of
the eyeball of humans and other vertebrates), bones, and
teeth. To create these structures, collagen molecules are
positioned in arrays called fibrils, producing what are known
as the D-periodic fibrillar collagens. Until now, technical
limitations prevented accurate structural studies of collagen
type II packing. A research team aided by the BioCAT 18- ID
beamline and the BioCARS 14-BM-C beamline at the APS has
remedied that situation by determining the molecular structure
of collagen type II in living tissues.
The Power of Proteins: Prion Diseases Demystified
It is hard to believe that a single protein can be responsible
for the damage inflicted by diseases such as human
Creutzfeldt-Jakob and bovine spongiform encephalopathy
(Mad Cow Disease). Yet the implicated protein, known as a
prion and only about 200 amino acids long, can initiate and
propagate a disease cycle just by changing its shape. A
collaborative research team has achieved a significant advance
in our understanding of the infectious power of the prion protein.
Getting to Know Cellulose
As humans continue to deplete the Earth’s supply of fossil fuels,
finding new sources of energy becomes a priority. Biomass, such
as cornhusks left after harvest, is one such alternative energy
source. Before efficient use can be made of such materials,
understanding how to break down cellulose—the fiber in human
nutrition and the main component of much biomass waste—is crucial.
With the help of the NE-CAT and BioCAT beamlines at the APS and
the SPring-8 (Japan) beamline BL38B1, an international research
team from Los Alamos National Laboratory, the University of Tokyo,
and the University of Grenoble has identified important new
features of cellulose structure. Their work provides important
new details that could be used in designing more efficient treatments
for cellulosic biomass.
Filling the Gaps in Collagen Structure
Collagens—we might take them for granted, but without them
there would be no way to build tissues of the heart, skin,
cornea, or bones. In much the same way that wood is used to
frame a house and form a structure for the overlying construction
materials, collagens are proteins used in the framing of mammalian
tissues, but gaining an accurate picture of their three-dimensional
structure in the body has proven more difficult. Thanks to work
by a research group based at the Illinois Institute of Technology
and using the BioCAT 18-ID beamline at the APS, a complete structure
for a collagen molecule—as it actually appears in the extracellular
matrix (ECM)—is now available.
The Correct Signals to Regulate Assembly in Bacteria
By employing x-ray scattering and electron microscopy
researchers using the BioCAT beamline were able to describe
—in stunning detail— a novel two-component mechanism for
assembling a protein associated with bacterial transcription.
Their work greatly advances our understanding of what happens
in normal and, by inference, diseased cells.
Storing the Power to Fly
Fruit flies beat their wings faster than their cellular
powerplants can generate the energy needed for flapping.
To resolve this energetic discrepancy, researchers used the
BioCAT beamline to obtain a series of x-ray photographs that
revealed the flies’ secret: A muscle protein used to power wings
acts like a spring, storing energy while stretched before
snapping back. Not only did this finding surprise researchers
who study muscle, but the results might also help scientists
better understand the human heart.