4. Consider a soluble lysosomal cargo protein. A. (2pts) What is the signal that
ID: 262707 • Letter: 4
Question
4. Consider a soluble lysosomal cargo protein. A. (2pts) What is the signal that is recognized to deliver proteins to the lysosome? B. (4pts) How could you change the protein sequence of the lysosomal cargo so that it is delivered and retained in the ER instead of delivered to the lysosome? C. (4pts) You add a Nuclear Localization Sequence (NLS) onto the C-terminus of the lysosomal cargo protein sequence, expecting it to be delivered to the nucleus. However, you observe that the mutant protein is still delivered to the lysosome. Please explain why the added NLS did not change the protein's destination. However to the lysosome.Explanation / Answer
Answer:-
Answer a:- The signal that is recognized to deliver proteins to the lysosome is Mannose 6- phosphate. The M6P residues on lysosomal proteins can be recognized by M6P-specific receptors in Golgi compartments. Recently researchers has discovered other mechanism known as M6P independent transport of lysosomal targeted proteins. They have found out that proteins known as sortilin and lysosomal integral membrane protein type 2 (LIMP-2) are responsible for carrying out M6P independent transport of lysosomal proteins.
Answer b. A newly synthesized protein must be properly folded and assembled before it leaves the ER. To make a protein stay in the ER we change induce mutations anywhere in the sequence that effects the proper folding of the protein. This way the protein will not leave the ER and will be retained there only. Another way to make a lysosomal protein stay in the ER is to somehow stop the binding of Mannose 6 phosphate to the protein as these are the signal sequences that are used to identify the proteins that need to be delivered to the lysosome. If this sequence doesn't have M6P then it will be retained in the ER.
Answer c. Proteins that are destined for lysosomes carry the N-terminal signal sequences which allow them to attach to the endoplasmic reticulum as they are being synthesized and they are then transported to the lysosome by the help of this N-terminal signal sequences. In this case, the NLS that we have attached to the C-terminus will not work because the transport is dependent on the sequence in the N-terminal as explained above. This is the reason why we see this mutant protein still being transported to the lysosome instead of the nucleus.
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