Lecture 11: SNAREs II

A set of flashcards covering membrane fusion machinery, including SNARE protein functions, animal knockout models, human genetic diseases like FHL4 and CEDNIK, and the mechanism of action of Botulinum and Tetanus toxins.

What are the three primary SNARE proteins mentioned that drive membrane fusion?

SNAP25, Syntaxin, and Synaptobrevin/VAMP.

Which protein is responsible for SNARE recycling using ATP hydrolysis?

NSF (N-ethylmaleimide-sensitive factor).

Identify the three temperature-sensitive Drosophila mutants used in the 1970s to study membrane fusion inhibitors.

shibire (dynamin), comatose (NSF), and paralytic ($\alpha$-subunit of voltage-gated sodium channel).

What cellular phenomenon occurs in comatose flies when they are shifted to a restrictive temperature?

Docked vesicles accumulate in large numbers under the plasma membrane.

What is the phenotype observed in knockout mice lacking the VAMP2 gene?

They die at birth and exhibit a loss of synaptic transmission.

How does the phenotype of Syntaxin 1A knockout mice differ from Syntaxin 1B knockout mice?

Syntaxin 1A knockouts show no gross abnormalities, whereas Syntaxin 1B knockouts die after birth with reduced synaptic transmission.

Which SNARE protein mutation is associated with CEDNIK syndrome (Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome)?

SNAP29.

What is the common clinical description for the babies born with heterozygous mutations in VAMP2?

Hypotonia, also known as "floppy baby syndrome."

According to the transcript, what is the effect of the $S75P$ mutation in VAMP2 on liposome fusion?

It slows the rate of liposome fusion.

Why is the $S75P$ mutation in VAMP2 classified as a dominant negative mutation?

Because the wild-type protein is not able to compensate for the variant, even in a $0.5\times WT : 0.5\times variant$ ratio.

What life-threatening immune condition is characterized by a "cytokine storm" and mutations in SNARE-related genes like Syntaxin 11?

Familial hemophagocytic lymphohistiocytosis (FHL).

Which specific SNARE protein mutation causes Familial hemophagocytic lymphohistiocytosis type 4 (FHL4)?

Syntaxin 11 (STX11).

What is unique about the structure of the Q-SNARE Syntaxin 11 (STX11) compared to others?

It does not have a transmembrane domain.

What is the consequence of mutations in Munc18-2 regarding the SNARE protein Syntaxin 11?

They cause FHL5 and drastically reduce the levels of STX11.

What is the estimated $LD_{50}$ of clostridial neurotoxins, making them the most potent biological toxins known?

$1-2\,ng/kg$.

Which bacterium is the cause of tetanus, and what is its common clinical name?

Clostridium tetani; commonly known as lockjaw.

Approximately how many people die from tetanus globally each year according to the 1808 Charles Bell reference?

Approximately 50,000 people.

What is considered a potential dietary source of botulism for infants under 6 months old?

Honey.

What are the three functional domains found in clostridial neurotoxins?

Protease domain, Translocation domain, and Targeting domain.

Clostridial neurotoxins act as proteases that are dependent on which metal ion?

$Zn^{2+}$ (Zinc).

Which SNARE protein is cleaved by Botulinum neurotoxin types A and E (BoNT/A and BoNT/E)?

SNAP25.

Which SNARE protein is cleaved by Tetanus neurotoxin (TeNT) and Botulinum neurotoxin types B, D, F, and G?

VAMP (Synaptobrevin).

How does the paralysis caused by Botulinum toxin differ from that caused by Tetanus toxin?

Botulinum toxin causes flaccid paralysis, while Tetanus toxin causes rigid paralysis.

Why is Tetanus toxin able to reach inhibitory neurons while Botulinum toxin typically remains at the neuromuscular junction?

Tetanus toxin retrotranslocates up the motor neuron to reach the inhibitory neurons of the central nervous system.

Name at least three non-cosmetic clinical uses for Botulinum toxin A.

Strabismus, blepharospasm, cervical dystonia, axillary hyperhidrosis, overactive bladder, and sialorrhea.

What is the target SNARE protein for most cosmetic products based on Botulinum A?

SNAP25.

Why can't medical treatments be effectively based on Tetanus toxin like they are for Botulinum toxin?

Because almost everybody is vaccinated against the Tetanus toxin.

What was the estimated valuation of the global Botulinum toxin market in 2019?

Nearly 5 billion dollars.

Which specific Botulinum toxin type is used in the product MYOBLOC for treating cervical dystonia?

Botulinum B (RimabotulinumtoxinB).

What is the primary sign mentioned as one of the first symptoms of infant botulism?

Droopy eyelids.