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6.14:

קולטנים קשורי-אנזים

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Biology
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JoVE Core Biology
Enzyme-linked Receptors

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קולטנים מסוימים יכולים לשמש גם כאנזימים, מולקולות המאיצות תגובות כימיות. דוגמה אחת כזו היא קולטן טירוזין קינאז, או RTK. כאשר מולקולת איתות, הליגנד, נקשרת, שני RTK קשורים עוברים דימריזציה, או הצמדות.תהליך זה מפעיל את אזורי הטירוזין על הקולטנים, אשר בתורם מעבירים קבוצת פוספט אל טירוזין ATP-מ בצד הנגדי של הדימר בתהליך הנקרא זרחון. ברגע שלכל הטירוזינים יש פוספטים מוצמדים, הדימר מופעל במלואו. עכשיו, סוגים שונים של חלבונים שליחים יכולים להתחבר לטירוזין מזורחן ספציפי ולעבור שינוי צורה מבני, ובך לפתוח נתיבים משלהם למעבר אותות שיובילו לתגובה תאית.

6.14:

קולטנים קשורי-אנזים

Enzyme-linked receptors are proteins which act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.

RTKs are also called neurotrophin (NT) receptors because they bind nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, NT-4/5, NT-6, and NT-7. The growth factors typically bind to an RTK subfamily of tropomyosin-related kinase receptors (Trk): Trk A, Trk B, and Trk C. Trk A is specific for NGF, NT-6, and NT-7. Trk B binds BDNF and NT-4/5, while Trk C is specific for NT-3. NT-3 can also bind with low affinity to Trk A and TrkB.

The Trk receptors have a single transmembrane domain, with a growth factor binding site on the extracellular portion and an enzyme activation site intracellularly. Trk receptors can be monomeric or dimerized, where two Trk receptors are bound together. To activate the receptor, a single growth factor molecule either binds two monomeric receptors, causing them to dimerize, or it binds both sites on a pre-dimerized receptor.

Once the receptors are bound, the tyrosines phosphorylate by pulling phosphates from ATP and donating them to each other, a process called “autophosphorylation.” This opens docking sites along the intracellular domain of the receptor. Each docking site is specific for different signaling proteins. This increases the variety of downstream effects these receptors regulate.

The interaction between NGF and Trk A has garnered attention for their role in the progression of Alzheimer’s disease. In this disorder, neurons develop amyloid plaques. Amyloid-beta is a cytotoxic fragment of the amyloid precursor protein, or APP. It is hypothesized that binding NGF to its Trk A receptor decreases the generation of amyloid-beta by joining APP to the Trk A receptor. This eliminates the ability of beta-secretase 1 (BACE1) to cleave APP into amyloid-beta. Furthermore, the Trk A receptor can shuttle APP to the Golgi where BACE1 enzymes are rare. In the brains of Alzheimer’s patients, the Trk A/APP complex is downregulated in areas important to learning and memory, like the hippocampus.

Suggested Reading

Lemmon, Mark A., and Joseph Schlessinger. “Cell Signaling by Receptor-Tyrosine Kinases.” Cell 141, no. 7 (June 25, 2010): 1117–34. [Source]

Willard, Stacey S., and Shahriar Koochekpour. “Glutamate, Glutamate Receptors, and Downstream Signaling Pathways.” International Journal of Biological Sciences 9, no. 9 (September 22, 2013): 948–59. [Source]